Triazolopyrimidine compounds and their use in treating cancer

ABSTRACT

The invention concerns compounds of Formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , X, Ring A, Ring B and Ring C have any of the meanings hereinbefore defined in the description; process for their preparation; pharmaceutical compositions containing them and their use in treating MCT4 mediated diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No.17/095,729, filed on Nov. 11, 2020, which is a Continuation of PCTPatent Application No. PCT/EP2019/062020, filed on May 10, 2019, whichclaims foreign priority of U.S. provisional Application No. 62/670,075,filed on May 11, 2018. Each of these applications is hereby incorporatedby reference herein in its entirety.

FIELD

The specification generally relates to triazolopyrimidine compounds andpharmaceutically acceptable salts thereof. These compounds and theirpharmaceutically acceptable salts selectively inhibit MCT4, and thespecification therefore also relates to the use of such compounds andsalts thereof to treat or prevent MCT4 mediated disease, includingcancer. The specification further relates to crystalline forms oftriazolopyrimidine compounds and pharmaceutically acceptable saltsthereof; pharmaceutical compositions comprising such compounds andsalts; kits comprising such compounds and salts, methods of manufactureof such compounds and salts, and to methods of treating MCT4 mediateddisease, including cancer, using such compounds and salts.

BACKGROUND

Monocarboxylate transporters are encoded by the SLC16 gene family. Thefamily is also known as the monocarboxylate transporter (MCT) familysince the first members to be identified were demonstrated to beresponsible for the proton-linked transport of monocarboxylates such asL-lactate, pyruvate and ketone bodies across the plasma membrane. Directdemonstration of proton-linked lactate and pyruvate transport has beendemonstrated for MCT1 (SLC16A1), MCT2 (SLC16A7), MCT3 (SLC16A8) and MCT4(SLC16A3). The nomenclature for the MCT family is taken from Halestrapand Price, Biochemical Journal (1999) 343: 281-299.

MCTs possess 12 transmembrane helices and functional expression requiresinteraction with single transmembrane domain chaperones known as CD147(also known as basigin and EMMPRIN) and embigin. CD147 acts as anessential chaperone to take MCT1 and MCT4 to the plasma membrane wherethe transporter and CD147 remain tightly associated (Kirk et al. (2000)EMBO J. 19: 3896-3904). Correct plasma membrane expression of MCT2 showsa strong preference for embigin over CD147 (Wilson et al (2005) J. Biol.Chem. 280: 27213-27221).

It is well established that tumours display altered metabolism (VanderHeiden (2011) Nat. Drug Dis. 10:671-684). Tumours are composed of welloxygenated (aerobic) and poorly oxygenated (hypoxic) regions. Comparedto normal cells, tumour cells have an increased dependency on theglycolytic pathway for ATP generation either via aerobic glycolysis (theWarburg effect) or anaerobic glycolysis as a consequence of tumourhypoxia. Highly proliferating tumours and hypoxic tumours appear to beparticularly dependent upon glycolysis to meet their energy andbiosynthetic requirements. Widespread clinical use of FDG-PET(Fluorodeoxyglucose Positron Emission Tomography)—PET scanning with thetracer fluorine-18 (F-18) fluorodeoxyglucose (FDG), has demonstratedthat this glycolytic phenotype is observed in a range of solid andhaematological tumours. As a result, FDG-PET can be used for diagnosis,staging, and monitoring treatment of cancers. FDG-PET combined withcomputer tomography has a >90% sensitivity and specificity for thedetection of metastases of most epithelial tumours (Mankoff et al.(2007) Clin. Cancer Res. 13:3460-3469).

A by-product of the increased glycolytic rates in tumours is theaccumulation of lactate. Intracellular lactate can be transported out oftumour cells via the monocarboxylate transporters (MCTs 1, 2, 3 & 4)(Halestrap and Price, Biochem J. (1999) 343: 291-299). Lactate that isproduced by tumour cells can be taken up by stromal and oxygenatedtumour cells (via the monocarboxylate transporters MCT1 and MCT2) toregenerate pyruvate that can be used to fuel oxidative phosphorylation(OXPHOS) (Koukouris et al., Cancer Res. (2006) 66; 632-637; Sonveaux etal., J. Clin. Invest. (2008) 118; 3930-3942). One of the key factors indriving the glycolytic phenotype of tumours is the activation ofhypoxia-inducible factor (HIF), a transcription factor that is activatedby hypoxic stress. MCT4 is a HIF target gene and is up-regulated byhypoxia and is required to export lactate from glycolytic tumours (Ullahet al. (2006) J. Biol. Chem. 281:9030-9037). The kinetic properties ofMCT4 are tuned to its role in exporting lactic acid derived fromglycolysis because its very high Km for pyruvate (150 mM) ensures thatpyruvate is not exported from the cell. This is essential because NADHderived from reduction of pyruvate to lactate is required to driveglycolytic flux (Halestrap and Wilson (2012) IUMBM Life 64: 109-119).

MCT4 is over-expressed in a range of solid tumours compared to normalepithelium including renal tumours (Fisel et al. (2013) Clin. CancerRes. 19: 5170-5181; Gerlinger et al. J. Pathol. 227: 146-156),pancreatic tumours (Back et al. (2014) Cell Rep. 9:2233-2249),colorectal tumours (Pinheiro et al., Virchows Arch. (2008) 452;139-146), HNSCC (Zhu et al. (2014) PLoS One 9:e87904), breast cancer(Doyen et al. (2014) Biochem. Biophys. Res. Commun. 451:54-61), prostatecancer (Pertega-Gomes et al. BMC Cancer (2011) 11:312) and liver cancer(Gao et al. (2015) J Cancer Res. 141: 1151-1162).

Recent data has indicated that lactate plays an important role inregulating immune cell function. Lactate has been shown to inhibit theactivity of immune effector cells such as T cells and NK cells. Lacticacid suppresses the proliferation and activation of human T cells exvivo (Fisher et al. (2007) Blood 109:3812-3819; Haas et al. (2015) PLoSBiol 13). Husain et al. have demonstrated that NK cells fromLDHA-depleted tumours showed improved cytolytic function and lactatetreatment of NK cells reduced their cytotoxic activity (Husain et al.(2013) J. Immunol. 191:1486-1495). Furthermore, Brand et al.demonstrated that in immunocompetent mice, knock-down of LDHA reducedlactic acid production and an increased infiltration of IFN-γ-producingT and NK cells was observed in tumours (Brand et al. (2016) Cell Metab.24:657-671). Lactate has also been shown to inhibit monocyte activationand dendritic cell differentiation (Gottfried et al. (2006) Blood107:2013-2021; Died et al. (2010) J. Immunol. 184:1200-1209) and alsoinduce M2 (immunosuppressive) tumour associated macrophage polarisation(Colegio et al. (2014) Nature 513:559-563). Taken together, these datasupport the hypothesis that lactate produced as a by-product of theglycolytic phenotype of tumours drives an immunosuppressive effect inthe tumour microenvironment.

Lactate accumulation in the tumour microenvironment is accompanied byacidosis (due to the co-transport with protons). A low pH in the tumourmicroenvironment has been associated with extracellular matrixdegradation and migration of tumour cells (Gillies and Gatenby (2015)Cancer J. 21: 88-96).

Potent inhibitors of MCT1/2 have been described in WO2004/065394 whichshows that in T-lymphocytes, lactate efflux occurs via MCT1, as smallmolecule inhibitors of MCT1 result in accumulation of intracellularlactate (Murray et al., Nat. Chem Biol. (2005) 1: 371-376).

However, there is also a need for inhibitors of MCT4 that inhibit thetransport of lactate into MCT4-dependent cells, demonstrate goodbioavailability and are suitable for dosing.

SUMMARY

Briefly, this specification describes, in part, a compound of Formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ and R² each independently represent hydrogen or methyl;    -   X represents CH₂ or O;    -   Ring A and Ring B each independently represent a ring selected        from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl,        wherein each of Ring A and Ring B are independently optionally        substituted with one or more substituents selected from C₁₋₃        alkyl and C₁₋₃ alkoxy;    -   Ring C represents a 5 to 9 membered monocyclic or bicyclic        saturated heterocycloalkyl optionally containing one or more        additional heteroatoms independently selected from O, N and S,        wherein Ring C is optionally substituted with one or more        substituents selected from C₁₋₃ alkyl, optionally substituted        with methoxy or hydroxyl; dioxo, C₀₋₂ alkyl-C(O)N(Me)₂,        C(O)C₁₋₂alkyl and S(O)₂C₁₋₂ alkyl.

This specification also describes, in part, a pharmaceutical compositionwhich comprises a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient.

This specification also describes, in part, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for use in therapy.

This specification also describes, in part, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for use in the treatmentof cancer.

This specification also describes, in part, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of cancer.

This specification also describes, in part, a method for treating cancerin a warm-blooded animal in need of such treatment, which comprisesadministering to the warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the X-ray powder diffraction (XRPD) pattern for Form A of(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine(Compound A, Example 62).

FIG. 2 shows the DSC for Form A of(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine(Compound A, Example 62).

FIG. 3 shows the in vivo activity of an MCT4 inhibitor (Example 62) incombination with VEGFR TKI (AZD2171, also known as cediranib) in a lungcancer xenograft model.

FIG. 4 shows the in vivo activity of an MCT4 inhibitor (Example 62) incombination with an α-CTLA4 antibody in a mouse syngeneic model.

FIG. 5 shows the in vivo activity of MCT4 inhibitor (Example 62) incombination with an αPD-1 antibody in a mouse syngeneic model.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Many embodiments of the invention are detailed throughout thespecification and w % ill be apparent to a reader skilled in the art.The invention is not to be interpreted as being limited to anyparticular embodiment(s) thereof.

In the first embodiment there is provided a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ and R² each independently represent hydrogen or methyl;    -   X represents CH₂ or O;    -   Ring A and Ring B each independently represent a ring selected        from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl,        wherein each of Ring A and Ring B are independently optionally        substituted with one or more substituents selected from C₁₋₃        alkyl and C₁₋₃ alkoxy;    -   Ring C represents a 5 to 9 membered monocyclic or bicyclic        saturated heterocycloalkyl optionally containing one or more        additional heteroatoms independently selected from O, N and S,        wherein the heterocycloalkyl is optionally substituted with one        or more substituents selected from C₁₋₃ alkyl, optionally        substituted with methoxy or hydroxyl; dioxo, C₀₋₂        alkyl-C(O)N(Me)₂, C(O)C₁₋₂ alkyl and S(O)₂C₁₋₂alkyl.

The term “heterocycloalkyl” means a 5 to 9 membered saturatednitrogen-containing non-aromatic ring (Ring C in Formula (I)) comprisingone or more additional heteroatoms independently selected from nitrogen,oxygen and sulphur. Examples of suitable heterocycloalkyl groups includemorpholinyl, piperazinyl, piperidinyl, thiomorpholinyl,diazabicyclooctanyl, octahydropyrrolo[1,2-a]pyrazinyl, pyrrolidinyl,diazepanyl, oxazepanyl and azepanyl. For the avoidance of doubt,substituents on the heterocycloalkyl ring may be linked via either acarbon atom or a heteroatom.

The term “dioxo” means two oxo substituents which are attached to thesame atom. Examples of dioxo substitution include instances where Ring Crepresents thiomorpholinyl, where the sulphur atom is substituted withtwo oxo groups, i.e. where Ring C is thiomorpholine-1,1-dioxide.

The prefix C_(p-q) in C_(p-q) alkyl and other terms (where p and q areintegers) indicates the range of carbon atoms that are present in thegroup, for example C₁₋₃ alkyl includes C₁ alkyl (methyl), C₂ alkyl(ethyl) and C₃ alkyl (propyl as n-propyl and isopropyl). In oneembodiment, the C₁₋₃ alkyl is methyl.

The term C_(p-q) alkoxy comprises —O—C_(p-q) alkyl groups. For example,C₁₋₃ alkoxy includes C₁ alkoxy (methoxy), C₂ alkoxy (ethoxy) and C₃alkoxy (propoxy as n-propoxy and isopropoxy). In one embodiment, theC₁₋₃ alkoxy is methoxy.

Where the term “optionally” is used, it is intended that the subsequentfeature may or may not occur. As such, use of the term “optionally”includes instances where the feature is present, and also instanceswhere the feature is not present. For example, a group “optionallysubstituted by one methoxy group” includes groups with and without amethoxy substituent.

The term “substituted” means that one or more hydrogens (for example oneor two hydrogens, or alternatively one hydrogen) on the designated groupis replaced by the indicated substituent(s) (for example one or twosubstituents, or alternatively one substituent), provided that anyatom(s) bearing a substituent maintains a permitted valency. Substituentcombinations encompass only stable compounds and stable syntheticintermediates. “Stable” means that the relevant compound or intermediateis sufficiently robust to be isolated and have utility either as asynthetic intermediate or as an agent having potential therapeuticutility. If a group is not described as “substituted”, or “optionallysubstituted”, it is to be regarded as unsubstituted (i.e. that none ofthe hydrogens on the designated group have been replaced).

The term “pharmaceutically acceptable” is used to specify that an object(for example a salt, dosage form, excipient) is suitable for use inpatients. An example list of pharmaceutically acceptable salts can befound in the Handbook of Pharmaceutical Salts: Properties, Selection andUse, P. H.

A further embodiment provides any of the embodiments defined herein (forexample the embodiment of claim 1) with the proviso that one or morespecific Examples (for instance, one, two or three specific Examples)selected from the group consisting of Examples 1, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86 and 87 is individually disclaimed.

In one embodiment, X represents CH₂. In another embodiment, X representsO.

In one embodiment, R¹ and R² both represent hydrogen. In anotherembodiment, R¹ and R² both represent methyl. In another embodiment, R¹represents hydrogen and R² represents methyl. In one embodiment, R¹ andR² both represent hydrogen or R¹ represents hydrogen and R² representsmethyl.

Ring A is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl andpyridazinyl.

Ring B is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl andpyridazinyl.

In Formula (I), Ring A is attached to the nitrogen of a pyrrolidine ringand to Ring B, and Ring B is attached to Ring A and to the group—C(R¹R²)-Ring C. Ring A and Ring B may be optionally further substitutedas defined herein. In one embodiment, the pyrrolidine ring and Ring Bare in para (i.e. 1,4) orientation on Ring A. In another embodiment,Ring A and the group —C(R¹R²)-Ring C are in para (i.e. 1,4) orientationon Ring B. In one embodiment, the pyrrolidine ring and Ring B are inpara (i.e. 1,4) orientation on Ring A and Ring A and the group—C(R¹R²)-Ring C are in para (i.e. 1,4) orientation on Ring B. In yetanother embodiment, the pyrrolidine ring and Ring B are in para (i.e.1,4) orientation on Ring A and Ring A and the group —C(R¹R²)-Ring C arein para (i.e. 1,4) orientation on Ring B and Ring A and Ring B arelinked to each other via a ring carbon and are linked to the remainderof the molecule via a ring carbon.

In one embodiment, at least one of Ring A or Ring B is selected frompyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl.

In one embodiment, Ring A and Ring B are each independently selectedfrom phenyl, pyridazinyl and pyrazinyl. In another embodiment, Ring Aand Ring B are each independently selected from phenyl and pyridazinyl.In another embodiment, Ring A is phenyl and Ring B is pyridazinyl. Inanother embodiment, Ring A is pyrazinyl and Ring B is phenyl.

In one embodiment, Ring A and Ring B are optionally substituted with oneor two substituents selected from C₁₋₃ alkyl and C₁₋₃ alkoxy. In oneembodiment, Ring A and Ring B are each independently optionallysubstituted by one substituent selected from C₁₋₃ alkyl and C₁₋₃ alkoxy.In one embodiment, Ring A and Ring B are each independently optionallysubstituted by one substituent selected from methyl and methoxy.

In one embodiment, Ring C represents a 5 to 7 membered monocyclicsaturated heterocycloalkyl ring. In another embodiment, Ring Crepresents an 8 or 9 membered bicyclic saturated heterocycloalkyl ring.The bicyclic heterocycloalkyl ring may be a bridged or fused bicyclicring.

In one embodiment, Ring C is selected from the group consisting ofmorpholinyl, piperazinyl, piperidinyl, thiomorpholinyl,diazabicyclooctanyl, octahydropyrrolo[1,2-a]pyrazinyl, pyrrolidinyl,diazepanyl, oxazepanyl and azepanyl.

In one embodiment, Ring C is selected from the group consisting ofmorpholin-4-yl, piperazin-4-yl, piperidin-1-yl, thiomorpholine-4-yl,3,8-diazabicyclo[3.2.1]octan-8-yl, octahydropyrrolo[1,2-a]pyrazin-2-yl,pyrrolidine-1-yl, 1,4-diazepan-1-yl, 1,4-oxazepan-4-yl, azepanyl-1-yl.

In one embodiment, Ring C is morpholinyl or piperazinyl. In oneembodiment, Ring C is morpholin-4-yl or piperazin-4-yl.

In one embodiment, Ring C is morpholinyl. In one embodiment, Ring C ismorpholin-4-yl.

In one embodiment, Ring C is piperazinyl. In one embodiment, Ring C ispiperazin-4-yl.

In one embodiment, Ring C is optionally substituted with one or more(e.g. one, two or three) substituents independently selected fromhydroxyl; ethyl optionally substituted with methoxy or hydroxyl; dioxo,C(O)N(Me)₂, CH₂C(O)N(Me)₂, C(O)Me and S(O)₂Me. In one embodiment, Ring Cis substituted with C(O)Me or methyl.

In one embodiment, Ring C is piperazin-4-yl-ethanone. In anotherembodiment, Ring C is 4-methyl-1-piperazinyl.

In one embodiment:

-   -   R¹ and R² are both hydrogen;    -   X represents CH₂ or O;    -   Ring A and Ring B each independently represent a ring selected        from phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl,        wherein each of Ring A and Ring B are independently optionally        substituted with one or more substituents selected from C₁₋₃        alkyl and C₁₋₃ alkoxy; Ring C represents a 5 to 9 membered        monocyclic or bicyclic saturated heterocycloalkyl optionally        containing one or more additional heteroatoms independently        selected from O, N and S, wherein the heterocycloalkyl is        optionally substituted with one or more substituents selected        from C₁₋₃ alkyl, optionally substituted with methoxy or        hydroxyl; dioxo, C₀₋₂ alkyl-C(O)N(Me)₂, C(O)C₁₋₂ alkyl and        S(O)₂C₁₋₂alkyl.

In one embodiment:

-   -   R¹ and R² are both hydrogen;    -   X represents O;    -   Ring A and Ring B are each independently selected from phenyl        and pyridazinyl;    -   Ring C represents morpholinyl or piperazinyl wherein the        piperazinyl is optionally substituted with C₁₋₃ alkyl,        optionally substituted with methoxy or hydroxyl; C₀₋₂        alkyl-C(O)N(Me)₂, C(O)C₁₋₂ alkyl and S(O)₂C₁₋₂ alkyl.

In one embodiment:

-   -   R¹ and R² are both hydrogen;    -   X represents CH₂;    -   Ring A and Ring B are each independently selected from phenyl,        pyridazinyl and pyrazinyl;    -   Ring C represents morpholinyl, piperazinyl or pyrazinyl wherein        the pyrazinyl or piperazinyl is optionally substituted with C₁₋₃        alkyl, optionally substituted with methoxy or hydroxyl; C₀₋₂        alkyl-C(O)N(Me)₂, C(O)C₁₋₂alkyl and S(O)₂C₁₋₂alkyl.

A further embodiment provides a compound of Formula (Ia):

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   R¹ and R² each independently represent hydrogen or methyl;    -   X represents CH₂ or O;    -   D, E, G, J, L, M, Q and R each independently represent N or CR³,        wherein no more than two of D, E, G and J represent N and        wherein no more than two of L, M, Q and R represent N;    -   R³ represents hydrogen, C₁₋₃ alkyl or C₁₋₃ alkoxy;    -   Ring C represents a 5 to 9 membered monocyclic or bicyclic        saturated heterocycloalkyl optionally containing one or more        additional heteroatoms independently selected from O, N and S,        wherein the heterocycloalkyl is optionally substituted with one        or more substituents selected from C₁₋₃ alkyl, optionally        substituted with methoxy or hydroxyl; dioxo, C₀₋₂        alkyl-C(O)N(Me)₂, C(O)C₁₋₂ alkyl and S(O)₂C₁₋₂alkyl.

In one embodiment, R¹ and R² both represent hydrogen. In anotherembodiment, R¹ and R² both represent methyl. In another embodiment, R¹represents hydrogen and R² represents methyl. In one embodiment, R¹ andR² both represent hydrogen or R¹ represents hydrogen and R² representsmethyl.

D, E, G and J each independently represent N or CR³, wherein no morethan two of D, E, G and J represent N.

L, M, Q and R each independently represent N or CR³, wherein no morethan two of L, M, Q and R represent N.

In one embodiment, D, E, G and J each independently represent CR³. Inanother embodiment, one of D, E, G and J represents N and the remaindereach independently represent CR³. In another embodiment, two of D, E, Gand J represent N and the remainder both independently represent CR³.

In one embodiment, L, M, Q and R each independently represent CR³. Inanother embodiment, one of L, M, Q and R represents N and the remaindereach independently represent CR³.

In another embodiment, two of L, M, Q and R represent N and theremainder both independently represent CR³.

In one embodiment, D, E, G and J each independently represent CR³ and L,M, Q and R each independently represent N or CR³, wherein no more thantwo of L, M, Q and R represent N. In one embodiment, one of D, E, G andJ represents N and the remainder each independently represent CR³ and L,M, Q and R each independently represent N or CR³, wherein no more thantwo of L, M, Q and R represent N. In one embodiment, two of D, E, G andJ represent N and the remainder both independently represent CR³ and L,M, Q and R each independently represent N or CR³, wherein no more thantwo of L, M, Q and R represent N.

In one embodiment, D, E, G and J represent N or CR³, wherein no morethan two of D, E, G and J represent N and L, M, Q and R eachindependently represent CR³. In one embodiment, D, E, G and J representN or CR³, wherein no more than two of D, E, G and J represent N and oneof L, M, Q and R represents N and the remainder each independentlyrepresent CR³. In one embodiment, D, E, G and J represent N or CR³,wherein no more than two of D, E, G and J represent N and two of L, M, Qand R represent N and the remainder both independently represent CR³.

In one embodiment, D, E, G and J each independently represent CR³ and L,M, Q and R each independently represent CR³.

In one embodiment, D, E, G and J each independently represent CR³ andone of L, M, Q and R represents N and the remainder each independentlyrepresent CR³.

In one embodiment, D, E, G and J each independently represent CR³ andtwo of L, M, Q and R represent N and the remainder both independentlyrepresent CR³.

In one embodiment, one of D, E, G and J represents N and the remaindereach independently represent CR³ and L, M, Q and R each independentlyrepresent CR³.

In one embodiment, one of D, E, G and J represents N and the remaindereach independently represent CR³ and one of L, M, Q and R represents Nand the remainder each independently represent CR³.

In one embodiment, one of D, E, G and J represents N and the remaindereach independently represent CR³ and two of L, M, Q and R represent Nand the remainder both independently represent CR³.

In one embodiment, two of D, E, G and J represent N and the remainderboth independently represent CR³ and L, M, Q and R each independentlyrepresent CR³.

In one embodiment, two of D, E, G and J represent N and the remainderboth independently represent CR³ and one of L, M, Q and R represents Nand the remainder each independently represent CR³.

In one embodiment, two of D, E, G and J represent N and the remainderboth independently represent CR³ and two of L, M, Q and R represent Nand the remainder both independently represent CR³.

In one embodiment, the ring containing D, E, G and J is a ring selectedfrom phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl. In oneembodiment, the ring containing D, E, G and J is a ring selected fromphenyl, pyridazinyl and pyrazinyl. In one embodiment, the ring isselected from phenyl and pyridazinyl.

In one embodiment, the ring containing L, M, Q and R is a ring selectedfrom phenyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl. In oneembodiment, the ring containing L, M, Q and R is a ring selected fromphenyl, pyridazinyl and pyrazinyl. In one embodiment, the ring isselected from phenyl and pyridazinyl.

In another embodiment, the ring containing D, E, G and J is phenyl andthe ring containing L, M, Q and R is pyridazinyl. In another embodiment,the ring containing D, E, G and J is pyrazinyl and the ring containingL, M, Q and R is phenyl.

In one embodiment, the ring containing D, E, G and J and the ringcontaining L, M, Q and R are each independently optionally substitutedwith one or two substituents, i.e. where R³ represents C₁₋₃ alkyl andC₁₋₃ alkoxy. In one embodiment, the ring containing D, E, G and J andthe ring containing L, M, Q and R are each independently optionallysubstituted with one substituent, i.e. where R³ represents C₁₋₃ alkyland C₁₋₃ alkoxy. In one embodiment, the ring containing D, E, G and Jand the ring containing L, M, Q and R are each independently optionallysubstituted with one substituent where R³ is selected from methyl andmethoxy.

In one embodiment, Ring C represents a 5 to 7 membered monocyclicsaturated heterocycloalkyl ring. In another embodiment, Ring Crepresents an 8 or 9 membered bicyclic saturated heterocycloalkyl ring.The bicyclic heterocycloalkyl ring may be a bridged or fused bicyclicring.

In one embodiment, Ring C is selected from the group consisting ofmorpholinyl, piperazinyl, piperidinyl, thiomorpholinyl,diazabicyclooctanyl, octahydropyrrolo[1,2-a]pyrazinyl, pyrrolidinyl,diazepanyl, oxazepanyl and azepanyl.

In one embodiment, Ring C is selected from the group consisting ofmorpholin-4-yl, piperazin-4-yl, piperidin-1-yl, thiomorpholine-4-yl,3,8-diazabicyclo[3.2.1]octan-8-yl, octahydropyrrolo[1,2-a]pyrazin-2-yl,pyrrolidine-1-yl, 1,4-diazepan-1-yl, 1,4-oxazepan-4-yl, azepanyl-1-yl.

In one embodiment, Ring C is morpholinyl or piperazinyl. In oneembodiment, Ring C is morpholin-4-yl or piperazin-4-yl.

In one embodiment, Ring C is morpholinyl. In one embodiment, Ring C ismorpholin-4-yl.

In one embodiment, Ring C is piperazinyl. In one embodiment, Ring C ispiperazin-4-yl.

In one embodiment, Ring C is optionally substituted with one or more(e.g. one, two or three) substituents independently selected fromhydroxyl; ethyl optionally substituted with methoxy or hydroxyl; dioxo,C(O)N(Me)₂, CH₂C(O)N(Me)₂, C(O)Me and S(O)₂Me. In one embodiment, Ring Cis substituted with C(O)Me or methyl.

In one embodiment, Ring C is piperazin-4-yl-ethanone. In anotherembodiment, Ring C is 4-methyl-1-piperazinyl.

In one embodiment:

-   -   R¹ and R² are both hydrogen;    -   X represents CH₂ or O;    -   D, E, G, J, L, M, Q and R each independently represent N or CR³,        wherein no more than two of D, E, G and J represent N and        wherein no more than two of L, M, Q and R represent N;    -   R³ represents hydrogen, C₁₋₃ alkyl or C₁₋₃ alkoxy;    -   Ring C represents a 5 to 9 membered monocyclic or bicyclic        saturated heterocycloalkyl optionally containing one or more        additional heteroatoms independently selected from O, N and S,        wherein the heterocycloalkyl is optionally substituted with one        or more substituents selected from C₁₋₃ alkyl, optionally        substituted with methoxy or hydroxyl; dioxo, C₀₋₂        alkyl-C(O)N(Me)₂, C(O)C₁₋₂ alkyl and S(O)₂C₁₋₂alkyl.

In one embodiment:

-   -   R¹ and R² are both hydrogen;    -   X represents O;    -   D, E, G, J, L, M, Q and R each independently represent N or CR³,        wherein no more than two of D, E, G and J represent N and        wherein no more than two of L, M, Q and R represent N;    -   R³ represents hydrogen, methyl or methoxy;    -   Ring C represents morpholinyl or piperazinyl wherein the        piperazinyl is optionally substituted with C₁₋₃ alkyl,        optionally substituted with methoxy or hydroxyl; C₀₋₂        alkyl-C(O)N(Me)₂, C(O)C₁₋₂ alkyl and S(O)₂C₁₋₂alkyl.

In one embodiment:

-   -   R¹ and R² are both hydrogen;    -   X represents CH₂;    -   D, E, G, J, L, M, Q and R each independently represent N or CR³,        wherein no more than two of D, E, G and J represent N and        wherein no more than two of L, M, Q and R represent N;    -   R³ is selected from hydrogen, methyl or methoxy;    -   Ring C represents morpholinyl, piperazinyl or pyrazinyl wherein        the pyrazinyl or piperazinyl is optionally substituted with C₁₋₃        alkyl, optionally substituted with methoxy or hydroxyl; C₀₋₂        alkyl-C(O)N(Me)₂, C(O)C₁₋₂ alkyl and S(O)₂C₁₋₂ alkyl.

A further embodiment provides a compound of Formula (Ib):

-   -   or a pharmaceutically acceptable salt thereof, wherein R¹, R²,        X, Ring A, Ring B and Ring C are as defined herein.

A further embodiment provides a compound of Formula (Ic):

-   -   or a pharmaceutically acceptable salt thereof, wherein R¹, R²,        X, D, E, G, J, L, M, Q, R and Ring C are as defined herein.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   (R)-4-((6′-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)-[3,3′-bipyridin]-6-yl)methyl)morpholine;-   (R)-2,5,7-trimethyl-6-((1-(6′-((4-methylpiperazin-1-yl)methyl)-[3,3′-bipyridin]-6-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-(4-(2-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)benzyl)morpholine;-   (R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyridin-2-yl)pyrazin-2-yl)methyl)morpholine;-   (R)-2,5,7-trimethyl-6-((1-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((6-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyridin-2-yl)pyridazin-3-yl)methyl)morpholine;-   6-(((R)-1-(2-(4-(((S)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-yl)methyl)morpholine;-   (R)-6-((1-(2-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(2-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   6-(((R)-1-(2-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)—N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)acetamide;-   (R)-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethanol;-   (R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethenone;-   (R)-6-((1-(2-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)morpholine;-   (R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(4-(2-((4-methylpiperazin-1-yl)methyl)pyrimidin-5-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridin-3-yl)methyl)morpholine;-   (R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyrazin-2-yl)methyl)morpholine;-   (R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine;-   (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;-   (S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;-   (R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   2,5,7-trimethyl-6-(((R)-1-(5-(4-(((3R,5S)-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   6-(((R)-1-(5-(4-(((R)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   6-(((R)-1-(5-(4-(((R)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   2,5,7-trimethyl-6-(((R)-1-(5-(4-(((2R,5R)-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   2,5,7-trimethyl-6-(((R)-1-(5-(4-(((2S,5R)-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   2,5,7-trimethyl-6-[[(3R)-1-[5-[4-(1-piperidylmethyl)phenyl]pyrazin-2-yl]pyrrolidin-3-yl]methyl]-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-6-((1-(5-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(5-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   6-(((R)-1-(5-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   2-{4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazin-1-yl}ethanol;-   (R)-6-((1-(5-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   {1-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperidin-4-yl}methanol;-   6-{[(3R)-1-(5-(4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}pyrazin-2-yl)pyrrolidin-3-yl]methyl)-2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidine;-   2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperidin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin-3-yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((6-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-3-yl)methyl)morpholine;-   6-(((R)-1-(5-(4-(((S)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-2-yl)methyl)morpholine;-   6-(((R)-1-(5-(4-(((S)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-(4-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine;-   2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin-3-yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)—N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)acetamide;-   (R)-2,5,7-trimethyl-6-((1-(6-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   N,N-dimethyl-4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazine-1-carboxamide;-   (R)-2,5,7-trimethyl-6-((1-(5-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(5-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)ethenone;-   (R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine;-   (R)-4-(4-(6-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyridazin-3-yl)benzyl)morpholine;-   (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;-   (S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;-   (R)-2,5,7-trimethyl-6-((1-(4-(6-(piperidin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;-   2,5,7-trimethyl-6-(((3R)-1-(4-(6-((3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;-   6-(((R)-1-(4-(6-(((R)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   6-(((R)-1-(4-(6-(((S)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine;-   (R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyrazin-2-yl)methyl)morpholine;-   (R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one;-   (R)-6-((1-(4-(6-((4-ethylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-6-((1-(4-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((6′-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)-[2,3′-bipyridin]-5-yl)methyl)morpholine;-   (R)-4-((6′-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)-[3,3′-bipyridin]-6-yl)methyl)morpholine;-   (R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine;-   1-[4-[[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]methyl]-1,4-diazepan-1-yl]ethenone;-   (R)-2,5,7-trimethyl-6-((1-(5-(4-(pyrrolidin-1-ylmethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((1-(5-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-2,5,7-trimethyl-6-((I-(5-(4-((4-methyl-1,4-diazepan-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)-1,4-oxazepane;-   (R)-6-((1-(4-(6-(azepan-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   4-[(1R)-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine;    and-   4-[(1S)-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound isselected from the group consisting of:

-   (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;-   (R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one;-   (R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;    and-   (R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound is(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine(also referred to as Compound A).

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound is(R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound is(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein the compound is(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine.

In one embodiment, the compound of Formula (I) is in the free base form.

Compounds and salts described in this specification may exist insolvated forms and unsolvated forms. For example, a solvated form may bea hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, atri-hydrate or an alternative quantity thereof. The inventionencompasses all such solvated and unsolvated forms of compounds ofFormula (I), particularly to the extent that such forms possess MCT4inhibitory activity, as for example measured using the tests describedherein.

Atoms of the compounds and salts described in this specification mayexist as their isotopes. The invention encompasses all compounds ofFormula (I) where an atom is replaced by one or more of its isotopes(for example a compound of Formula (I) where one or more carbon atom isan ¹¹C or ¹³C carbon isotope, or where one or more hydrogen atoms is a²H or ³H isotope, or where one or more nitrogen atoms is a ¹⁵N isotopeor where one of more oxygen atoms is an ¹⁷O or ¹⁸O isotope).

Compounds and salts described in this specification may exist inoptically active or racemic forms by virtue of one or more asymmetriccarbon atoms. The invention includes any optically active or racemicform of a compound of Formula (I) which possesses MCT4 inhibitoryactivity, as for example measured using the tests described herein. Thesynthesis of optically active forms may be carried out by standardtechniques of organic chemistry well known in the art, for example bysynthesis using optically active materials or by resolution of a racemicform.

Therefore, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically acceptable salt thereof, which is a singleoptical isomer being in an enantiomeric excess (% e.e.) of ≥95%, ≥98% or≥99%. In one embodiment, the single optical isomer is present in anenantiomeric excess (% e.e.) of ≥99%.

Some of the compounds of Formula (I) may be crystalline and may havemore than one crystalline form. It is to be understood that theinvention encompasses any crystalline or amorphous form, or mixturesthereof, which possess properties useful in MCT4 inhibitory activity. Itis well known how to determine the efficacy of a crystalline oramorphous form by the standard tests described hereinafter.

It is generally known that crystalline materials may be analysed usingconventional techniques such as, for example, X-ray powder diffraction(hereinafter XRPD) analysis and Differential Scanning Calorimetry(hereinafter DSC).

As an example, the compound of Example 62 exhibits crystallinity and acrystalline form, Form A, has been identified.

Accordingly, a further aspect of the disclosure is Form A of Compound A(Example 62).

According to the disclosure there is provided a crystalline form, FormA, of Compound A which has an XRPD pattern with at least one specificpeak at about 2-theta=7.8°, measured using CuKα radiation.

According to the disclosure there is provided a crystalline form, FormA. of Compound A which has an XRPD pattern with at least one specificpeak at about 2-theta=19.0°, measured using CuKα radiation.

According to the disclosure there is provided a crystalline form, FormA. of Compound A which has an XRPD pattern with at least two specificpeaks at about 2-theta=7.8° and 19.0°, measured by CuKα radiation.

According to the disclosure there is provided a crystalline form, FormA. of Compound A which has an XRPD pattern with specific peaks at about2-theta=7.8, 9.2, 9.5, 10.4, 11.6, 15.8, 18.3 19.0, 22.3 and 25.3°,measured by CuKα radiation.

According to the disclosure there is provided crystalline form, Form A,of Compound A which has an XRPD pattern substantially the same as theXRPD pattern shown in FIG. 1 , measured by CuKα radiation.

According to the disclosure there is provided crystalline form, Form A,of Compound A which has an XRPD pattern with at least one specific peakat 2-theta=7.8° plus or minus 0.2° 2-theta, measured by CuKα radiation.

According to the disclosure there is provided a crystalline form, FormA. of Compound A which has an XRPD pattern with at least one specificpeak at 2-theta=19.0° plus or minus 0.2° 2-theta, measured by CuKαradiation.

According to the disclosure there is provided a crystalline form, FormA, of Compound A which has an XRPD pattern with at least two specificpeaks at 2-theta=7.8° and 19.0° wherein said values may be plus or minus0.2° 2-theta, measured by CuKα radiation.

According to the disclosure there is provided a crystalline form, FormA, of Compound A which has an XRPD pattern with specific peaks at2-theta=7.8, 9.2, 9.5, 10.4, 11.6, 15.8, 18.3 19.0, 22.3 and 25.3°wherein said values may be plus or minus 0.2° 2-theta, measured by CuKαradiation.

DSC analysis of Compound A, Form A shows a melting endotherm with anonset of about 210.2° C. and a peak at about 213.2° C. (FIG. 2 ).

Thus DSC analysis shows Compound A. Form A is a high melting solid withan onset of melting at about 210.2° C. and a peak at about 213.2° C.

When it is stated that the present disclosure relates to a crystallineform of Form A of Compound A, the degree of crystallinity isconveniently greater than about 60%, more conveniently greater thanabout 80%, preferably greater than about 90% and more preferably greaterthan about 95%. Most preferably the degree of crystallinity is greaterthan about 98%.

It will be understood that the 2-theta values of the XRPD pattern mayvary slightly from one machine to another or from one sample to another,and so the values quoted are not to be construed as absolute.

It is known that an XRPD pattern may be obtained which has one or moremeasurement errors depending on measurement conditions (such asequipment or machine used). In particular, it is generally known thatintensities in an XRPD pattern may fluctuate depending on measurementconditions. Therefore it should be understood that Compound A, Form A ofthe present disclosure is not limited to the crystals that provide XRPDpatterns identical to the XRPD pattern shown in FIG. 1 , and anycrystals providing XRPD patterns substantially the same as that shown inFIG. 1 fall within the scope of the present disclosure. A person skilledin the art of XRPD is able to judge the substantial identity of XRPDpatterns.

Persons skilled in the art of XRPD will understand that the relativeintensity of peaks can be affected by, for example, grains above 30microns in size and non-unitary aspect ratios, which may affect analysisof samples. The skilled person will also understand that the position ofreflections can be affected by the precise height at which the samplesits in the diffractometer and the zero calibration of thediffractometer. The surface planarity of the sample may also have asmall effect. Hence the diffraction pattern data presented are not to betaken as absolute values. (Jenkins, R & Snyder, R. L. ‘Introduction toX-Ray Powder Diffractometry’ John Wiley & Sons 1996; Bunn, C. W. (1948),Chemical Crystallography, Clarendon Press, London; Klug, H. P. &Alexander, L. E. (1974), X-Ray Diffraction Procedures).

Generally, a measurement error of a diffraction angle in an X-ray powderdiffractogram is approximately plus or minus 0.2° 2-theta, and suchdegree of a measurement error should be taken into account whenconsidering the XRPD pattern in FIG. 1 and when reading Table A.Furthermore, it should be understood that intensities might fluctuatedepending on experimental conditions and sample preparation (preferredorientation).

The compounds of Formula (I) include one or more chiral centres. To theextent a structure or chemical name in this specification does notindicate chirality, the structure or name is intended to encompass anysingle stereoisomer (i.e. any single chiral isomer) corresponding tothat structure or name, as well as any mixture of stereoisomers (e.g. aracemate). It is well-known in the art how such optically-active formscan be prepared. For example, a single stereoisomer can be obtained byisolating it from a mixtures of isomers (e.g. a racemate) using, forexample, chiral chromatographic separation. In other embodiments, asingle stereoisomer is obtained through direct synthesis from, forexample, a chiral starting material.

Compounds of Formula (I), where X represents O, may for example beprepared by the reaction of a compound of Formula (II):

or a salt thereof, with a compound of Formula (III):

or a salt thereof, where W is a suitable leaving group, for example Cl,Br, I or OTf, and R¹, R², Ring A, Ring B and Ring C are as defined inany of the embodiments herein. The reaction is conveniently performed ina suitable solvent (for example 2-methyltetrahydrofuran) in the presenceof a base (for example cesium carbonate) and in the presence of asuitable catalyst (for example Ruphos Pd 3^(rd) Generation) and ligand(for example Ruphos) at a suitable temperature (for example in the range60° C. to 80° C.).

Alternatively, depending on the nature of Ring A, the compounds ofFormula (I), or pharmaceutically acceptable salt thereof, may also beprepared by reaction of a compound of Formula (II), or salt thereof, anda compound of Formula (III), or salt thereof, using standard aromaticsubstitution conditions, well known to those skilled in the art, forexample with a suitable base (for example diisopropylethylamine) in asuitable solvent (for example 1-butanol) at a suitable temperature (forexample in the range of 60° C. to 120° C.).

Compounds of Formula (II) and (III), and salts thereof, are thereforeuseful as intermediates in the preparation of the compounds of Formula(I) and provide a further embodiment.

The compounds of Formula (II) may for example be prepared by thefollowing scheme, Scheme 1:

wherein PG is a suitable nitrogen protecting group, for example Boc.

Step 1: Performed using a suitable nucleophile (for example benzoicacid) in the presence of a suitable base (for example KOH) in a suitablesolvent (for example DMF) at a suitable temperature (for example in therange of 20° C. to 50° C.).

Step 2: Performed using a suitable cyclisation substrate (for example3-methyl-1H-1,2,4-triazol-5-amine) in a suitable solvent (for exampleAcOH) at a suitable temperature (for example in the range of 70° C. to90° C.).

Step 3: Performed under standard hydrolysis conditions, well known tothose skilled in the art, for example 1M NaOH (aq) in EtOH at RT.

Step 4: Performed using standard conditions well known to those skilledin the art. The reaction may be performed using standard Mitsunobuconditions with a suitable alcohol substrate (for exampletert-butyl-3-hydroxypyrrolidine-1-carboxylate) with triphenylphosphineand DIAD in THF at RT.

Step 5: Performed using standard deprotection conditions well known tothose skilled in the art. For example, when PG is Boc the reaction maybe performed using 4M HCl in 1,4-dioxane in MeOH at RT.

Compounds of Formula (III), where R¹ and R² are hydrogen, may forexample be prepared by reacting a compound of Formula (IV)

or a salt thereof with a suitable chlorinating reagent (for exampletrichloroisocyanuric acid) in a suitable solvent (for exampledichloroethane) followed by reacting with a suitable Ring C based amine(for example morpholine) at a suitable temperature (for example at RT),wherein W is a suitable leaving group, for example Cl, Br, I or OTf, andRing A, Ring B and Ring C are as defined in any of the embodimentsherein. In one embodiment Ring A is phenyl and Ring B is pyradazinyl.

Compounds of Formula (I), where X represents CH₂, may for example beprepared by the reaction of compounds of Formula (III), or a saltthereof, where R¹, R², Ring A, Ring B and Ring C are as defined in anyof the embodiments herein, with a compound of Formula (V)

or salt thereof. The reaction is conveniently performed in a suitablesolvent (for example 1,4-dioxane) in the presence of a base (for examplecesium carbonate) and in the presence of a suitable catalyst (forexample Ruphos Pd 3^(rd) Generation) and ligand (for example Ruphos) ata suitable temperature (for example 60° C. to 90° C.).

Compounds of Formula (V) are therefore also useful as intermediates inthe preparation of the compounds of Formula (I) and provide a furtherembodiment.

The compounds of Formula (V) may for example be prepared by thefollowing scheme, Scheme 2:

wherein PG is a suitable nitrogen protecting group, for example Boc andY is a suitable leaving group, for example Cl, Br, I or OMs.

Step 1: Performed using conditions that convert OH into a suitableleaving group, for example if Br is chosen as leaving group then thereaction may be performed using conditions well known to those skilledin the art for example with triphenylphosphine, tetrabromomethane, inDCM in a temperature range of 0° C. to RT.

Step 2: Performed using a suitable nucleophile (for examplepentane-2,4-dione) in the presence of a suitable base (for examplepotassium carbonate) in a suitable solvent (for example DMF) at asuitable temperature (for example in the range of 60° C. to 80° C.).

Step 3: Performed using a suitable cyclisation substrate (for example3-methyl-1H-1,2,4-triazol-5-amine) in a suitable solvent (for exampleAcOH) at a suitable temperature (for example in the range of (70° C. to90° C.).

Step 4: Performed using standard deprotection conditions well known tothose skilled in the art. For example, when PG is Boc the reaction maybe performed using 4M HCl in 1,4-dioxane in MeOH at RT.

Alternatively, compounds of Formula (I), where X represents CH₂, may beprepared by reacting a compound of Formula (VI)

or salt thereof, where W is a suitable leaving group, for example Cl,Br, I or OTf and Ring A is as defined in any of the embodiments herein,with a compound of Formula (VII)

or salt thereof, where Z is a suitable leaving group, for example,pinacol boronate ester, boronic acid or organotin and R¹, R², Ring B andRing C are as defined in any of the embodiments herein. When Z ispinacol boronate ester then the reaction is conveniently performed in asuitable solvent (for example a mixture of 1,4-dioxane and water) in thepresence of a base (for example cesium carbonate) and in the presence ofa suitable catalyst (for example Xphos Pd 2^(nd) Generation) at asuitable temperature (for example 60° C. to 90° C.). In one embodiment,R¹ and R² represent hydrogen, Ring A is pyrazinyl, Ring B is phenyl andRing C is 4-methyl-1-piperazinyl.

The compounds of Formula (VI), or salt thereof, may be prepared byreacting a compound of Formula (V), or salt thereof, with Ring A usingstandard aromatic substitution chemistry. Ring A will have a suitableleaving group (for example chlorine or bromine) and the reaction isconveniently performed in a suitable solvent (for example 1-butanol) inthe presence of a suitable base (for example diisopropylethylamine) at asuitable temperature (for example 60° C. to 120° C.). Alternatively, thecompounds of Formula (VI), or salt thereof, may be prepared by reactinga compound of Formula (V), or salt thereof, with Ring A using standardcross coupling conditions. Ring A will have a suitable leaving group(for example chlorine, bromine or iodine) in a suitable solvent (forexample 1,4-dioxane) in the presence of a base (for example cesiumcarbonate) and in the presence of a suitable catalyst (for exampleRuphos Pd 3^(nd) Generation) at a suitable temperature (for example 60°C. to 90° C.).

Alternatively, compounds of Formula (I), where X represents CH₂, may beprepared by reaction of a compound with Formula (VIII)

or salt thereof, with a suitable Ring C based amine, where Ring A, RingB and Ring C are as defined in any of the embodiments herein. Thereaction may be performed under standard conditions, well known to thoseskilled in the art, for example with triethylamine in THF at 60° C.

Alternatively, compounds of Formula (I), where X represents CH₂, may beprepared by reaction of a compound with Formula (IX)

or salt thereof, with a suitable Ring C based amine, where Ring A, RingB and Ring C are as defined in any of the embodiments herein. Thereaction may be performed under standard conditions, well known to thoseskilled in the art, for example with sodium triacetoxyborohydride, AcOHin DCM at RT.

It will be appreciated that certain of the various ring substituents inthe compounds of the present disclosure may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the disclosure. For example compounds of Formula (I) may beconverted into further compounds of Formula (I) by standard aromaticsubstitution reactions or by conventional functional groupmodifications. Such reactions and modifications include, for example,introduction of a substituent by means of an aromatic substitutionreaction, reduction of substituents, alkylation of substituents andoxidation of substituents. The reagents and reaction conditions for suchprocedures are well known in the chemical art.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

In any of the embodiments where a compound of Formula (II) to (IX) or asalt thereof is mentioned it is to be understood that such salts do notneed to be pharmaceutically acceptable salts.

Compounds of Formula (I), and any intermediates used to make these, canbe prepared by methods similar to those shown in the Examples section.

Biological Assays

The following in vitro assays were used to measure the effects of thecompounds described herein.

Throughout the description of the assays the following abbreviationshave been used: BCECFAM=2′,7′-Bis-(2-Carboxyethyl)-5-(and-6)-Carboxyfluorescein,Acetoxymethyl Ester; DMSO=Dimethyl Sulphoxide; FBS=Foctal Bovine Serum;HBSS═Hanks Balanced Salt Solution;HEPES=4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; OD=OpticalDensity; RPMI=Roswell Park Memorial Institute 1640 Medium.

Compound efficacy within the assays was determined via measurement of anIC₅₀ value (the concentration of test compound that inhibited 50% ofbiological activity). IC₅₀ values were calculated using a smartfittingmodel within the Screener (Genedata AG) analysis package.

Rationale:

MCT4 is predominantly expressed in normal skeletal muscle and isupregulated in a range of solid tumours where it has a role infacilitating the efflux of lactate from the cell thereby preventingintracellular acidification. Thus inhibition of MCT4 activity representsa potential therapeutic opportunity in an oncology setting. MCT1 is aclosely related monocarboxylate transporter and as such a keyselectivity target for MCT4 inhibitors. Even though MCT4 is primarilyinvolved in cellular efflux of lactate it is possible to drive influx oflactate in an in vitro system as described for assay systems (b) and (d)below.

The purpose of these tests is to identify compounds which affect lactateefflux in a natively glycolytic cell-line predominantly expressing MCT4,and the transport of lactate into cells within the following in vitroassay systems:

-   -   a) SK-Br-3 cells (ATCC HTB-30)—a natively glycolytic human        breast adenocarcinoma line predominantly expressing MCT4        (confirmed by Western blotting)    -   b) NCI-H358 cells (ATCC CRL-5807)—a human lung adenocarcinoma        line predominantly expressing MCT4, a small amount of MCT2 and        no MCT1 (confirmed by Western blotting)    -   c) K562 cells (ATCC CCL-243)—a human erythroleukemia line        predominantly expressing MCT1, a small amount of MCT2 and no        MCT4 (confirmed by Western blot)    -   d) INS-1 MCT4 cells (parental INS-1 line gifted to AstraZeneca        from the University of Geneva, Switzerland)—a rat pancreatic        beta-cell line natively null for all MCT isoforms and engineered        in-house to stably express human MCT4 (confirmed by Western        blot).

Assay System (a):

Compounds of Formula I in 100% DMSO were added to empty 384 well assayplates (Costar #3712) via acoustic dispensing (120 nl/well over aconcentration range). SK-Br-3 cells (ATCC HTB-30) were seeded into theassay plates—directly onto the test compound—at a density of 4000cells/well, in 40 μl RPMI (Sigma #R0883) medium containing 1% Lglutamine (Sigma #G7513) and 20% FBS (Sigma #F7524). Assay plates werelidded and incubated for 4 hours at 37° C. and 5% CO₂.

Following incubation with test compound, 5 μl of media was transferredto a secondary 384 well assay plate (Costar #3712) using an automatedtip-based pipetting platform (CyBio Felix). The amount of lactic acidpresent in the media was quantified via a commercial lactate detectionkit (Trinity Biotech #735-10) employing the following coupled-enzymaticprinciple: Lactic acid is converted to pyruvate and H₂O₂ by lactateoxidase; in the presence of the H₂O₂ formed, peroxidase catalyzes theoxidative condensation of a chromogen precursor to produce a coloureddye with an absorption maximum at 540 nm (increasing absorbance beingdirectly proportional to increasing lactate within the sample). Theabsorbance was then measured on an automated microplate reader(PerkinElmer EnVision) using a 535 nm filter and OD values normalised tocontrol wells—treated with either DMSO (maximum assay signal) orchemistry related to that described in this patent (minimum assaysignal)—before fitting concentration response curves to determine anIC₅₀ value.

Assay Systems (b), (c):

Compounds of Formula I in 100% DMSO were added to empty 384 well assayplates (Costar #3683) via acoustic dispensing (90 nl/well over aconcentration range).

NCI-H358 cells (ATCC CRL-5807) or K562 cells (ATCC CCL-243) weredefrosted directly from cryopreservation, washed and re-suspended inHBSS (Gibco #14170) with 1 mM [final] HEPES (Gibco #15630).

Cells were loaded with the pH sensitive dye BCECF AM (Invitrogen #B1150)before being washed to remove excess dye and seeded into the assayplates—directly onto the test compound—at a density of 15,000 cells/well(NCI-H358) or 30,000 cells/well (K562), in 30 μl HBSS with 1 mM [final]HEPES. Assay plates were lidded and spun in a plate centrifuge at 170 gfor 1 minute. Plates were then wrapped in foil and incubated in the darkfor 1 hour at room temperature.

Following incubation with test compound, 10 μl of 25 mM Sodium-L-Lactate(Sigma #L7022) made up in HBSS with 1 mM final HEPES was directly addedinto 30 g media within the test wells—resulting in 6.25 mM final. Thisaddition was performed directly on the FLIPR Tetra platform (MolecularDevices) as part of a real-time kinetic read protocol. The cellularfluorescence using the filter set Ex470-495_Em515-575 was measuredovertime and the change from base-line (pre-lactate addition) to‘lactate addition+80 seconds’ was recorded. A percentage change frombase-line was calculated for each test well and values normalised tocontrol wells—treated with either DMSO (maximum assay signal) orchemistry related to that described in this patent (minimum assaysignal)—before fitting concentration response curves to determine anIC₅₀ value.

Assays System (d):

Compounds of Formula I in 100% DMSO were added to empty 384 well assayplates (Costar #3683) via acoustic dispensing (90 nl/well over aconcentration range).

INS-1 MCT4 cells were generated through transfection of the parentalcell background with the following DNA sequence, inserted into apcDNA3.1 (ThermoFisher #V79020) mammalian expression vector:

(SEQ ID NO: 1) atgggaggggccgtggtggacgagggccccacaggcgtcaaggcccctgacggcggctggggctgggccgtgctcttcggctgtttcgtcatcactggcttctcctacgccttccccaaggccgtcagtgtcttcttcaaggagctcatacaggagtttgggatcggctacagcgacacagcctggatctcctccatcctgctggccatgctctacgggacaggtccgctctgcagtgtgtgcgtgaaccgctttggctgccggcccgtcatgcttgtggggggtctctttgcgtcgctgggcatggtggctgcgtccttttgccggagcatcatccaggtctacctcaccactggggtcatcacggggttgggtttggcactcaacttccagccctcgctcatcatgctgaaccgctacttcagcaagcggcgccccatggccaacgggctggcggcagcaggtagccctgtcttcctgtgtgccctgagcccgctggggcagctgctgcaggaccgctacggctggcggggcggcttcctcatcctgggcggcctgctgctcaactgctgcgtgtgtgccgcactcatgaggcccctggtggtcacggcccagccgggctcggggccgccgcgaccctcccggcgcctgctagacctgagcgtcttccgggaccgcggctttgtgctttacgccgtggccgcctcggtcatggtgctggggctcttcgtcccgcccgtgttcgtggtgagctacgccaaggacctgggcgtgcccgacaccaaggccgccttcctgctcaccatcctgggcttcattgacatcttcgcgcggccggccgcgggcttcgtggcggggcttgggaaggtgcggccctactccgtctacctcttcagcttctccatgttcttcaacggcctcgcggacctggcgggctctacggcgggcgactacggcggcctcgtggtcttctgcatcttctttggcatctcctacggcatggtgggggccctgcagttcgaggtgctcatggccatcgtgggcacccacaagttctccagtgccattggcctggtgctgctgatggaggcggtggccgtgctcgtcgggcccccttcgggaggcaaactcctggatgcgacccacgtctacatgtacgtgttcatcctggcgggggccgaggtgctcacctcctccctgattttgctgctgggcaacttcttctgcattaggaagaagcccaaagagccacagcctgaggtggcggccgcggaggaggagaagctccacaagcctcctgcagactcgggggtggacttgcgggaggtggagcatttcctgaaggctgagcctgagaaaaacggggaggtggttcacaccccggaaacaagtgtctga

The resultant cell pool was continually cultured at 37° C. and 5% CO₂under antibiotic selection in RPMI (Sigma #R0883) medium containing 1% Lglutamine (Sigma #G7513), 10% FBS (Sigma #F7524), 10 mM [final] HEPES(Gibco #15630), 0.004% β-Mercaptoethanol (Sigma #M6250) and 100 μg/mlGeneticin (ThermoFisher #10131027). An individual clone was selected andexpanded before being cryopreserved in a number of individual vials forcontinued use. Prior to testing in the biological assay, an individualINS-1 MCT4 cryovial was defrosted and continually passaged over a numberof weeks—in the Geneticin selection media described previously—to obtainthe requisite cell number. At the point of test, cells were detectedfrom the surface of the culture flasks, pooled, washed and re-suspendedin HBSS (Gibco #14170) with 1 mM [final] HEPES (Gibco #15630).

Cells were loaded with the pH sensitive dye BCECF AM (Invitrogen #B1150)before being washed to remove excess dye and seeded into the assayplates—directly onto the test compound—at a density of 15.000cells/well, in 30 μl HBSS with 1 mM [final] HEPES. Assay plates werelidded and spun in a plate centrifuge at 170 g for 1 minute. Plates werethen wrapped in foil and incubated in the dark for 1 hour at roomtemperature.

Following incubation with test compound, 10 μl of 25 mM Sodium-L-Lactate(Sigma #L7022) made up in HBSS with 1 mM [final] HEPES was directlyadded into 30 μl media within the test wells—resulting in 6.25 mM[final]. This addition was performed directly on the FLIPR Tetraplatform (Molecular Devices) as part of a real-time kinetic readprotocol. The cellular fluorescence using the filter setEx470-495_Em515-575 was measured over time and the change from base-line(pre-lactate addition) to ‘lactate addition+80 seconds’ was recorded. Apercentage change from base-line was calculated for each test well andvalues normalised to control wells—treated with either DMSO (maximumassay signal) or chemistry related to that described in this patent(minimum assay signal)—before fitting concentration response curves todetermine an IC₅₀ value.

The following in vivo assays were used to measure the effects of thecompounds described herein in combination with other agents.

Human Lung Cancer Xenograft Model—VEGFR TKI Combination

The in vivo efficacy of MCT4 inhibitors has been tested in humanxenograft models. The NSCLC cell line NCI H358 can be grown as asubcutaneous xenograft in female nude mice and tumour volume calculatedfrom bilateral caliper measurements. For efficacy studies three millionNCI H358 cells were inoculated sub-cutaneously onto the left flank ofthe animal in a volume of 0.1 ml serum free media (RPMI) and matrigel.Animals were assigned into treatment groups 14 days after cellimplantation and received either AZD2171 (3 mg/kg QD) (Wedge et al.,(2005) Cancer Res. 65:4389-4400), a compound of Formula (I) (100 mg/kgBID) or the combination of both by oral gavage. A vehicle control of0.5% hydroxy propyl methyl cellulose/0.1% Tween 80 was dosed twice dailygiven orally. Dosing was continued for 17 days and tumour volume, bodyweight and tumour condition were recorded twice weekly for the durationof the study.

The results of testing Example 62 are shown in FIG. 3 . VEGF inhibitorAZD2171 was effective demonstrating a 33% (p≤0.001) tumour regressioncompared to the vehicle group. The combination of AZD2171 with the MCT4inhibitor Example 62 demonstrated a more dramatic response equaling 72%tumour regression (p≤0.001 compared to the control) which was alsosignificantly different (p=0.013) from the AZD2171 given alone. Groupsizes at study termination: Vehicle n=11; Example 62 n=4; AZD2171 n=10;AZD2171 plus Example 62 n=9.

Mouse Syngeneic Model—α-CTLA4 Antibody Combination and αPD-1 AntibodyCombinations

The in vivo efficacy of MCT4 inhibitors has been tested in murinesyngeneic models. To test the selective impact of MCT4 inhibitors ofFormula (I), MCT1 was knocked-out (KO) of the MC38 syngeneic cell linemodel using CRISPR precise genome editing. The MC38 MCT1 KO murinecolorectal cell line can be grown sub-cutaneously in female C57.Bl6 miceand tumour volume calculated from bilateral caliper measurements. Forefficacy studies, ten million cells were inoculated subcutaneously ontothe left flank of the animal in a volume of 0.1 ml serum free DMEMmedia. Animals were randomised by bodyweight at the time of cellimplantation and treatment started the following day. In the first ofthese studies shown in FIG. 4 , monotherapy treatment arms receivedeither a compound of Formula (I) (100 mg/kg BID) by oral gavage orαCTLA4 antibody (anti-CTLA-4 9D9 mlgG1 antibody, described inWO200712373) (10 mg/kg twice weekly) intraperitoneally. Combinationgroups consisted of a compound of Formula (I) (100 or 10 mg/kg PO BID)with αCTLA4 antibody (10 mg/kg IP twice weekly). In the second of thesestudies shown in FIG. 5 , monotherapy treatment arms received either acompound of Formula (I) (30 mg/kg PO BID) with αPD-1 antibody (from BioX Cell, Catalogue #BE0146, Lot 665417s1, 6.78 mg/mL) (10 mg/kg IP twiceweekly). In both studies dosing was continued for up to 6 weeks andtumour volume, body weight and tumour condition were recorded threetimes weekly. Vehicle was 0.5% hydroxy propyl methyl cellulose/0.1%Tween 80 given twice daily by oral gavage with PBS/a given twice weeklyintraperitoneally in both studies.

The results of testing Example 62 in the first syngeneic study are shownin FIG. 4 . Individual tumour growth profiles are shown with animalstaken off study using time to event criteria based on a maximum tumourvolume of 1.5 cm³, tumour condition or animal welfare limits. Due toanimals coming off study during the later stages of the experiment,GeoMean percentage inhibition values were calculated on Day 15. Comparedto vehicle control, Example 62 monotherapy (100 mg/kg) delivered60.0%^(p≤0.05) growth inhibition on that day. Monotherapy αCTLA4 (10mg/kg) was ineffective with 6.1% S. The combination of Example 62 (10and 100 mg/kg) with αCTLA4 antibody showed 67.4%^(p≤0.01) and82.2%^(p≤0.01) inhibition respectively, with the Example 62 (100 mg/kgBID) plus αCTLA4 antibody combination reaching statistical significance(p=0.0311) from Example 62 (100 mg/kg BID) given alone. Group sizes onDay 15: Vehicle n=12; Example 62 (100 mg/kg) n=11; αCTLA4 Antibody (10mg/kg) n=11; Example 62 (100 mg/kg) plus αCTLA4 antibody n=12; Example62 (10 mg/kg) plus αCTLA4 antibody n=9.

For the second syngeneic study testing Example 62 the results are shownin FIG. 5 . Again, individual tumour growth profiles are shown withanimals taken off study using time to event criteria based on a maximumtumour volume of 1.5 cm³, tumour condition or animal welfare limits. Dueto animals reaching the time to event endpoint at different times duringthe later stages of the experiment GeoMean percentage inhibition valueswere calculated on Day 13. Compared to vehicle control, Example 62monotherapy (30 mg/kg) delivered 30.1%^((NS)) growth inhibition on thatday. Monotherapy αPD-1 (10 mg/kg) efficacy was similar, delivering33.4%^(NS) inhibition. The combination of Example 62 (30 mg/kg) withαPD-1 antibody was more effective than the monotherapies showing82.3%^(p≤0.001) growth inhibition. Group sizes on Day 13: Vehicle n=8;Example 62 (30 mg/kg) n=10; αPD-1 antibody (10 mg/kg) n=11. Example 62(30 mg/kg) plus PD-1 antibody n=10.

It should be noted that the spider plots shown in FIGS. 4 and 5represent individual animal tumour growth data, comparing vehiclecontrol growth with treatment groups.

The following data, from assays a) to d), was generated for the Examples(the pIC50 values reported are the calculated mean result of at leastthree repeat experiments, except for Example 32, marked *, where thepIC50 value is the calculated mean result of two repeat experiments):

MCT4 MCT4 MCT1 MCT4 lactate efflux FLIPR FLIPR FLIPR Example pIC50 pIC50pIC50 pIC50 No. (SKBR3) (H358) (K562) (INS-1) 1 9.5 — — — 4 9.2 7.4 — —5 9.3 7.9 — — 6 9.2 8.1 — — 7 9.5 — — — 8 9.2 7.6 — — 9 9.3 7.8 <4.7 —10 9.3 7.5 — — 11 9.5 8.1 — — 12 8.4 — — — 13 8.6 — — — 14 8.7 — — — 159.0 — — — 16 9.3 7.5 — — 17 9.6 — — — 18 9.2 — — — 19 9.7 8.1 — — 20 9.37.4 — — 21 8.9 7.7 — — 22 9.0 — — — 23 9.4 8.2 — — 24 9.0 — — — 25 9.1 —— — 26 9.6 — — — 27 9.2 7.7 — — 28 9.6 — — — 29 9.5 7.9 <4.8 8.6 30 7.6— — — 31 8.5 7.3 — — 32 8.9* — — — 33 8.6 — — — 34 8.8 7.2 <4.6 — 35 9.27.8 <4.6 — 36 9.3 — <4.6 — 37 9.4 8.2 — — 38 8.4 7.5 — — 39 8.6 — — — 408.9 7.2 — — 41 9.1 — <4.6 — 42 9.1 8.0 <4.6 8.2 43 9.2 7.7 — — 44 9.2 —— — 45 9.7 — — — 46 9.7 — — — 47 8.7 8.0 — — 48 8.8 8.0 — — 49 9.2 8.1 —— 50 9.3 7.8 <4.6 — 51 9.3 8.1 — — 52 9.7 8.0 — — 53 9.2 7.6 — — 54 9.48.1 — — 55 9.6 8.0 — — 56 9.2 7.7 — — 57 8.4 6.9 — — 58 9.2 7.9 <4.6 —59 8.8 7.7 <4.6 7.8 60 9.4 8.1 4.9 8.3 61 9.0 8.2 — — 62 8.9 8.2 <4.68.7 63 6.6 — — — 64 8.8 7.3 <4.6 7.8 65 8.5 7.0 <4.6 7.3 66 8.7 7.3 <4.67.6 67 8.7 7.2 <4.6 7.3 68 8.5 7.0 <4.6 7.3 69 8.7 7.9 <4.6 8.5 70 9.28.3 <4.6 8.8 71 8.6 7.3 <4.6 7.7 72 8.6 7.1 <4.6 7.3 73 8.5 7.3 <4.6 7.574 8.7 8.0 <4.6 8.7 75 8.5 7.9 <4.6 8.5 76 8.7 — <4.6 — 77 8.4 7.8 — —78 8.6 8.2 — — 79 9.5 — — — 80 8.5 7.7 — — 81 8.5 7.8 5.3 8.5 82 8.6 7.9— — 83 9.1 — — — 84 9.0 8.1 <4.6 8.4 85 8.9 7.7 <4.6 8.2 86 8.6 7.9 <4.68.5 87 8.9 7.9 <4.6 8.4 dash “—” = not tested

The data shows that the compounds described herein affect both lactateefflux from a tumour cell line predominantly expressing MCT4 and in theappropriate conditions, inhibit transport of lactate into MCT4-dependentcells, and are therefore useful as MCT4 inhibitors.

Compounds may be further selected on the basis of further biological orphysical properties which may be measured by techniques known in the artand which may be used in the assessment or selection of compounds fortherapeutic or prophylactic application.

As a result of their MCT4 inhibitory activity, the compounds of Formula(I), and pharmaceutically acceptable salts thereof are expected to beuseful in therapy.

The term “therapy” is intended to have its normal meaning of dealingwith a disease in order to entirely or partially relieve one, some orall of its symptoms, or to correct or compensate for the underlyingpathology. The term “therapy” also includes “prophylaxis” unless thereare specific indications to the contrary. The terms “therapeutic” and“therapeutically” should be interpreted in a corresponding manner.

The term “prophylaxis” is intended to have its normal meaning andincludes prophylaxis whereby the disease has already developed and thepatient is temporarily or permanently protected against exacerbation orworsening of the disease or the development of new symptoms associatedwith the disease.

The term “treatment” is used synonymously with “therapy”. Similarly theterm “treat” can be regarded as “applying therapy” where “therapy” is asdefined herein.

Where “cancer” is mentioned, this includes both non-metastatic cancerand also metastatic cancer, such that treating cancer involves treatmentof both primary tumours and also tumour metastases.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in therapy.

In one embodiment there is provided the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment of adisease mediated by MCT4. In one embodiment, the disease mediated byMCT4 is cancer. In one embodiment the cancer is selected from the groupconsisting of colorectal cancer, glioblastoma, gastric cancer, ovariancancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia,acute myeloid leukaemia, head and neck squamous cell carcinoma, breastcancer, prostate cancer, bladder cancer, hepatocellular carcinoma, renalcancer, thyroid cancer, pancreatic cancer, small cell lung cancer andnon-small cell lung cancer.

In one embodiment the cancer is non-small cell lung cancer.

In one embodiment the cancer is lung adenocarcinoma.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of a disease mediated by MCT4. In oneembodiment, the disease mediated by MCT4 is cancer. In one embodiment,the cancer is selected from the group consisting of colorectal cancer,glioblastoma, gastric cancer, ovarian cancer, diffuse large B-celllymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, headand neck squamous cell carcinoma, breast cancer, prostate cancer,bladder cancer, hepatocellular carcinoma, renal cancer, thyroid cancer,pancreatic cancer, small cell lung cancer and non-small cell lungcancer.

In one embodiment the cancer is non-small cell lung cancer.

In one embodiment the cancer is lung adenocarcinoma.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of cancer.

In one embodiment there is provided a method for treating a disease inwhich inhibition of MCT4 is beneficial in a warm-blooded animal in needof such treatment, which comprises administering to said warm-bloodedanimal a therapeutically effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof. In one embodiment, thedisease is cancer.

In one embodiment, the cancer is selected from the group consisting ofcolorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuselarge B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloidleukaemia, head and neck squamous cell carcinoma, breast cancer,prostate cancer, bladder cancer, hepatocellular carcinoma, renal cancer,thyroid cancer, pancreatic cancer, small cell lung cancer and non-smallcell lung cancer.

In one embodiment the cancer is non-small cell lung cancer.

In one embodiment the cancer is lung adenocarcinoma.

In one embodiment there is provided a method for treating cancer in awarm-blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

Tumours that selectively express MCT4 over MCT1 have an increasedlikelihood of responding to treatment with a MCT4 inhibitor. Therefore,patients whose tumours express MCT1 at a low level are likely to respondbetter to an MCT4 inhibitor than those patients whose tumours expressMCT1 at a higher level. Generally, patients whose tumours have a highMCT4:MCT1 expression ratio (due to the low level of MCT1 expression),are likely to show a better response, so evaluating the relativeexpression levels of both MCT1 and MCT4 provides a means for selectingpatients for treatment with a MCT4 inhibitor. Methods for determiningthe relative expression levels of MCT1 and MCT4 are known in the art andare described in WO2010/089580, herein incorporated by reference.

In one embodiment, there is provided a method of treating cancercomprising (i) testing a tumour sample obtained from a patient sufferingfrom or likely to suffer from cancer for selective expression of MCT4over MCT1 and (ii) administering to the patient having the tumour whichselectively expresses MCT4 over MCT1, a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In one embodiment, there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer in a patient wherein the cancer tumour selectively expresses MCT4over MCT1.

In one embodiment, there is provided use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of cancer in a patient wherein the cancertumour selectively expresses MCT4 over MCT1.

In one embodiment, there is provided a method for treating cancer in awarm-blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein the cancer tumour selectively expresses MCT4 overMCT1.

The term “therapeutically effective amount” refers to an amount of acompound of Formula (I) as described in any of the embodiments hereinwhich is effective to provide “therapy” in a subject, or to “treat” adisease or disorder in a subject. In the case of cancer, thetherapeutically effective amount may cause any of the changes observableor measurable in a subject as described in the definition of “therapy”,“treatment” and “prophylaxis” above. For example, the effective amountcan reduce the number of cancer or tumour cells; reduce the overalltumour size; inhibit or stop tumour cell infiltration into peripheralorgans including, for example, the soft tissue and bone; inhibit andstop tumour metastasis; inhibit and stop tumour growth; relieve to someextent one or more of the symptoms associated with the cancer; reducemorbidity and mortality; improve quality of life; or a combination ofsuch effects. An effective amount may be an amount sufficient to deceasethe symptoms of a disease responsive to inhibition of MCT4 activity. Forcancer therapy, efficacy in vivo can, for example, be measured byassessing the duration of survival, time to disease progression (TTP),the response rates (RR), duration of response, and/or quality of life.As recognized by those skilled in the art, effective amounts may varydepending on route of administration, excipient usage, and co-usage withother agents. For example, where a combination therapy is used, theamount of the compound of Formula (I) or pharmaceutically acceptablesalt described in this specification and the amount of the otherpharmaceutically active agent(s) are, when combined, jointly effectiveto treat a targeted disorder in the animal patient. In this context, thecombined amounts are in a “therapeutically effective amount” if theyare, when combined, sufficient to decrease the symptoms of a diseaseresponsive to inhibition of MCT4 activity as described above. Typically,such amounts may be determined by one skilled in the art by, forexample, starting with the dosage range described in this specificationfor the compound of Formula (I) or pharmaceutically acceptable saltthereof and an approved or otherwise published dosage range(s) of theother pharmaceutically active compound(s).

“Warm-blooded animals” include, for example, humans.

The anti-cancer treatment described in this specification may be usefulas a sole therapy, or may involve, in addition to administration of thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,conventional surgery, radiotherapy or chemotherapy; or a combination ofsuch additional therapies. Such conventional surgery, radiotherapy orchemotherapy may be administered simultaneously, sequentially orseparately to treatment with the compound of Formula (I) or apharmaceutically acceptable salt thereof.

Where a combination therapy is administered “simultaneously”, thisincludes treatment of a patient with a single dosage form (e.g. atablet) comprising both a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof and an additional anti-cancer substance; andalso simultaneous dosing of separate dosage forms each separatelycomprising one of the respective combination partners.

Where a combination therapy is administered “sequentially” or“separately”, this includes treatment of a patient with a first dosageform (e.g. a tablet) comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, followed by treatment of thesame patient with a second dosage form comprising an additionalanti-cancer substance; or treatment of a patient with a single dosageform (e.g. a tablet) comprising a particular anti-cancer substance,followed by treatment of the same patient with a second dosage formcomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof. The interval between the sequential or separate doses maybe judged by a skilled practitioner with reference to the information inthis specification.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered before surgery.

Administration of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, before surgery to entirely or partially removea cancer may be referred to as “neo-adjuvant therapy”. In such ascenario, the goal of administering the compound of Formula (I), or apharmaceutically acceptable salt thereof is generally to reduce the sizeof the target tumour in order to increase the chances of a successfulresection. As such, the length of time the compound of Formula (I), or apharmaceutically acceptable salt thereof is dosed before surgery may bejudged by a skilled practitioner with reference to the informationwithin this specification.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered after surgery.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered in combination with at least oneadditional anti-cancer substance.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered simultaneously, sequentially orseparately with at least one additional anti-cancer substance.

The anti-cancer treatment defined herein may be applied as a soletherapy or may involve, in addition to the compounds of thespecification, conventional surgery or radiotherapy or chemotherapy.Such chemotherapy may include one or more of the following categories ofanti-tumour agents:

-   -   (i) other antiproliferative/antineoplastic drugs and        combinations thereof, as used in medical oncology, such as        alkylating agents (for example cis-platin, oxaliplatin,        carboplatin, cyclophosphamide, nitrogen mustard, melphalan,        chlorambucil, busulphan, temozolamide and nitrosoureas);        antimetabolites (for example gemcitabine and antifolates such as        fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,        methotrexate, pemetrexed, cytosine arabinoside, and        hydroxyurea); antitumour antibiotics (for example anthracyclines        like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,        idarubicin, mitomycin-C, dactinomycin and mithramycin);        antimitotic agents (for example vinca alkaloids like        vincristine, vinblastine, vindesine and vinorelbine and taxoids        like taxol and taxotere and polokinase inhibitors); and        topoisomerase inhibitors (for example epipodophyllotoxins like        etoposide and teniposide, amsacrine, topotecan and        camptothecin);    -   (ii) antiangiogenic agents such as those which inhibit the        effects of vascular endothelial growth factor, for example the        anti-vascular endothelial cell growth factor antibody        bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine        kinase inhibitor such as sorafenib, axitinib, pazopanib,        sunitinib and cediranib;    -   (iii) immunotherapy approaches, including for example ex vivo        and in vivo approaches to increase the immunogenicity of patient        tumour cells, such as transfection with cytokines such as        interleukin 2, interleukin 4 or granulocyte-macrophage colony        stimulating factor, approaches to decrease T-cell anergy,        approaches using transfected immune cells such as        cytokine-transfected dendritic cells, approaches using        cytokine-transfected tumour cell lines and approaches using        anti-idiotypic antibodies. Specific examples include monoclonal        antibodies targeting PD-1 (e.g. nivolumab and pembrolizumab),        PD-L1 (e.g. durvalumab and atezolizumab), CTLA4 (e.g.        tremelimumab and ipilimumab) or CD73 (e.g. oleclumab), as well        as CD40 ligand fusion proteins and GITR ligand fusion proteins;    -   (iv) inhibitors of lactate transporters, including for example        MCT1 inhibitors such as AZD3965;    -   (v) agents that target tumour metabolism including those that        inhibit GLS1, Complex I, mitochondrial pyruvate carrier        inhibitors.

Therefore, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically acceptable salt thereof, and at least oneadditional anti-tumour substance, for use in the treatment of cancer. Inone embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered in combination with anadditional anti-tumour substance. In one embodiment there is oneadditional anti-tumour substance. In one embodiment there are twoadditional anti-tumour substances. In one embodiment there are three ormore additional anti-tumour substances.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance for use in the simultaneous, separate orsequential treatment of cancer. In one embodiment there is provided acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for use in the treatment of cancer, where the compound of Formula (I),or a pharmaceutically acceptable salt thereof, is administeredsimultaneously, separately or sequentially with an additionalanti-tumour substance.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof and at least one additionalanti-tumour substance, wherein the amounts of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, and the additionalanti-tumour substance are jointly effective in producing an anti-cancereffect.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof, and simultaneously,separately or sequentially administering at least one additionalanti-tumour substance to said warm-blooded animal, wherein the amountsof the compound of Formula (I), or pharmaceutically acceptable saltthereof, and the additional anti-tumour substance are jointly effectivein producing an anti-cancer effect.

In any embodiment the additional anti-tumour substance is selected fromthe group consisting of one or more of the anti-tumour substances listedunder points (i)-(v) above.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of PD-1antibodies (e.g. nivolumab and pembrolizumab), PD-L1 antibodies (e.g.durvalumab and atezolizumab), CTLA4 antibodies (e.g. tremelimumab andipilimumab), CD73 antibodies (e.g. oleclumab), CD40 ligand fusionproteins and GITR ligand fusion proteins, for use in the treatment ofcancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of PD-L1antibodies (e.g. durvalumab and atezolizumab), for use in the treatmentof cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and durvalumab for use in thetreatment of cancer.

In one embodiment, the cancer is non-small cell lung cancer. In oneembodiment, the cancer is lung adenocarcinoma.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered simultaneously, separately orsequentially with at least one additional anti-tumour substance selectedfrom the group consisting of PD-1 antibodies (e.g. nivolumab andpembrolizumab), PD-L1 antibodies (e.g. durvalumab and atezolizumab),CTLA4 antibodies (e.g. tremelimumab and ipilimumab), CD73 antibodies(e.g. oleclumab), CD40 ligand fusion proteins and GITR ligand fusionproteins.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered simultaneously, separately orsequentially with at least one additional anti-tumour substance selectedfrom the group consisting of PD-L1 antibodies (e.g. durvalumab andatezolizumab).

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered simultaneously, separately orsequentially with durvalumab.

In one embodiment, the cancer is non-small cell lung cancer. In oneembodiment, the cancer is lung adenocarcinoma.

In one embodiment there is provided use of a compound of Formula (I), ora pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of cancer, where the compound of Formula(I), or a pharmaceutically acceptable salt thereof is administeredsimultaneously, separately or sequentially with at least one additionalanti-tumour substance selected from the group consisting of PD-1antibodies (e.g. nivolumab and pembrolizumab), PD-L1 antibodies (e.g.durvalumab and atezolizumab), CTLA4 antibodies (e.g. tremelimumab andipilimumab), CD73 antibodies (e.g. oleclumab), CD40 ligand fusionproteins and GITR ligand fusion proteins. In one embodiment there isprovided use of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for thetreatment of cancer, where the compound of Formula (I), or apharmaceutically acceptable salt thereof is administered simultaneously,separately or sequentially with at least one additional anti-tumoursubstance selected from the group consisting of PD-L1 antibodies (e.g.durvalumab and atezolizumab).

In one embodiment, there is provided use of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of cancer, where the compound of Formula(I), or a pharmaceutically acceptable salt thereof, is administeredsimultaneously, separately or sequentially with durvalumab.

In one embodiment the cancer is non-small cell lung cancer. In oneembodiment the cancer is lung adenocarcinoma.

In one embodiment, there is provided a method for treating cancer in awarm-blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, simultaneously, separately or sequentially with at leastone additional anti-tumour substance selected from the group consistingof PD-1 antibodies (e.g. nivolumab and pembrolizumab), PD-L1 antibodies(e.g. durvalumab and atezolizumab), CTLA4 antibodies (e.g. tremelimumaband ipilimumab), CD73 antibodies (e.g. oleclumab), CD40 ligand fusionproteins and GITR ligand fusion proteins.

In one embodiment, there is provided a method for treating cancer in awarm-blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, simultaneously, separately or sequentially with at leastone additional anti-tumour substance selected from the group consistingof PD-L1 antibodies (e.g. durvalumab and atezolizumab).

In one embodiment, there is provided a method for treating cancer in awarm-blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, simultaneously, separately or sequentially withdurvalumab.

In one embodiment the cancer is non-small cell lung cancer. In oneembodiment the cancer is lung adenocarcinoma.

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I) and at least one additionalanti-tumour substance, for use in the treatment of cancer. In oneembodiment the pharmaceutical composition also comprises at least onepharmaceutically acceptable excipient. In one embodiment the anti-tumoursubstance is an anti-neoplastic agent. According to a further embodimentthere is provided a kit comprising:

-   -   a) A compound of Formula (I), or a pharmaceutically acceptable        salt thereof, in a first unit dosage form;    -   b) A further additional anti-tumour substance in a further unit        dosage form;    -   c) Container means for containing said first and further unit        dosage forms; and optionally    -   d) Instructions for use.

The compounds of Formula (I), and pharmaceutically acceptable saltsthereof, may be administered as pharmaceutical compositions, comprisingone or more pharmaceutically acceptable excipients.

Therefore, in one embodiment there is provided a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient. The compositions may be in a form suitable for oral use (forexample as tablets, lozenges, hard or soft capsules, aqueous or oilysuspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous or intramusculardosing), or as a suppository for rectal dosing. The compositions may beobtained by conventional procedures using conventional pharmaceuticalexcipients, well known in the art. Thus, compositions intended for oraluse may contain, for example, one or more colouring, sweetening,flavouring and/or preservative agents.

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable excipient,for use in therapy.

In one embodiment there is provided a pharmaceutical compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable excipient,for use in the treatment of cancer. In one embodiment, said cancer isselected from the group consisting of colorectal cancer, glioblastoma,gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chroniclymphocytic leukaemia, acute myeloid leukaemia, head and neck squamouscell carcinoma, breast cancer, prostate cancer, bladder cancer,hepatocellular carcinoma, renal cancer, thyroid cancer, pancreaticcancer, small cell lung cancer and non-small cell lung cancer.

In one embodiment the cancer is non-small cell lung cancer.

In one embodiment the cancer is lung adenocarcinoma.

The compound of Formula (I) will normally be administered to awarm-blooded animal at a unit dose within the range 2.5-5000 mg/m² bodyarea of the animal, or approximately 0.05-100 mg/kg, and this normallyprovides a therapeutically-effective dose. A unit dose form such as atablet or capsule will usually contain, for example 0.1-500 mg of activeingredient. The daily dose will necessarily be varied depending upon thehost treated, the particular route of administration, any therapiesbeing co-administered, and the severity of the illness being treated.

EXAMPLES

Aspects of the present disclosure can be further defined by reference tothe following non-limiting examples, which describe in detailpreparation of certain compounds and intermediates of the presentdisclosure and methods for using compounds of the present disclosure. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, can be practiced without departing fromthe scope of the present disclosure.

Unless stated otherwise, starting materials were commercially available.All solvents and commercial reagents were of laboratory grade and wereused as received.

General Experimental

The invention will now be illustrated in the following Examples inwhich, generally:

-   -   (i) operations were carried out at room temperature (rt), i.e.        in the range 17 to 25° C. and under an atmosphere of an inert        gas such as N₂ or Ar unless otherwise stated;    -   (ii) in general, the course of reactions was followed by thin        layer chromatography (TLC) and/or analytical high performance        liquid chromatography (HPLC or UPLC) which was usually coupled        to a mass spectrometer (LCMS). The reaction times that are given        are not necessarily the minimum attainable;    -   (iii) when necessary, organic solutions were dried over        anhydrous MgSO₄ or Na₂SO₄, work-up procedures were carried out        using traditional phase separating techniques or by using SCX as        described in (xiii), evaporations were carried out either by        rotary evaporation in vacuo or in a Genevac HT-4/EZ-2 or Biotage        V10;    -   (iv) yields, where present, are not necessarily the maximum        attainable, and when necessary, reactions were repeated if a        larger amount of the reaction product was required;    -   (v) in general, the structures of the end-products of the        Formula (I) were confirmed by nuclear magnetic resonance (NMR)        and/or mass spectral techniques; electrospray mass spectral data        were obtained using a Waters Acquity UPLC coupled to a Waters        single quadrupole mass spectrometer acquiring both positive and        negative ion data, and generally, only ions relating to the        parent structure are reported; proton NMR chemical shift values        were measured on the delta scale using either a Bruker AV500        spectrometer operating at a field strength of 500 MHz, a Bruker        AV400 operating at 400 MHz or a Bruker AV300 operating at 300        MHz. Unless otherwise stated, NMR spectra were obtained at 500        MHz in d6-dimethylsulfoxide. The following abbreviations have        been used (and derivatives thereof, e.g. dd, doublet of        doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet;        m, multiplet; br, broad; qn, quintet; p, pentet    -   (vi) unless stated otherwise compounds containing an asymmetric        carbon and/or sulfur atom were not resolved;    -   (vii) intermediates were not necessarily fully purified but        their structures and purity were assessed by TLC, analytical        HPLC/UPLC, and/or NMR analysis and/or mass spectrometry;    -   (viii) unless otherwise stated, flash column chromatography        (fcc) was performed on Merck Kieselgel silica (Art. 9385) or on        reversed phase silica (Fluka silica gel 90 C18) or on Silicycle        cartridges (40-63 μm silica, 4 to 330 g weight) or on Puriflash        cartridges (50 μm silica, 4 to 330 g weight) or on Grace resolv        cartridges (4 to 120 g) or on RediSep Rf 1.5 Flash columns or on        RediSep Rf high performance Gold Flash columns (150 to 415 g        weight) or on RediSep Rf Gold C18 Reversed-phase columns (20-40        μm silica) either manually or automated using an Isco CombiFlash        Companion system or similar system;    -   (ix) preparative reverse phase HPLC (RP HPLC) was performed on        C18 reversed-phase silica typically using a Waters XSelect CSH        C18 or Phenomenex Gemini-NX axia Prep C18 OBD column (5 μm        silica, 30 mm diameter, 100 mm length) using decreasingly polar        mixtures as eluent, for example [containing 0.1% formic acid or        0.3-0.5% aqueous ammonium hydroxide (d=0.91)] as solvent A and        acetonitrile as solvent B; a typical procedure would be as        follows: a solvent gradient over 10-20 minutes, at 40-50 mL per        minute, from a 95:5 mixture of solvents A and B respectively to        a 5:95 mixture of solvents A and B (or alternative ratio as        appropriate).    -   (x) the following analytical UPLC methods were used; in general,        reverse-phase C18 silica was used with a flow rate of 1        mL/minute and detection was by Electrospray Mass Spectrometry        and by UV absorbance recording a wavelength range of 220-320 nm.        Analytical UPLC was performed on CSH C18 reverse-phase silica,        using a Waters XSelect CSH C18 column with dimensions 2.1×50 mm        and particle size 1.7 micron). Gradient analysis was employed        using decreasingly polar mixtures as eluent, for example        decreasingly polar mixtures of water (containing 0.1% formic        acid or 0.1% ammonia) as solvent A and acetonitrile as        solvent B. A typical 2 minute analytical UPLC method would        employ a solvent gradient over 1.3 minutes, at approximately 1        mL per minute, from a 97:3 mixture of solvents A and B        respectively to a 3:97 mixture of solvents A and B.    -   (xi) where certain compounds were obtained as an acid-addition        salt, for example a mono-hydrochloride salt or a        di-hydrochloride salt, the stoichiometry of the salt was based        on the number and nature of the basic groups in the compound,        the exact stoichiometry of the salt was generally not        determined, for example by means of elemental analysis data,    -   (xii) where reactions refer to the use of a microwave, one of        the following microwave reactors were used: Biotage Initiator,        Personal Chemistry Emrys Optimizer, Personal Chemistry        Smithcreator or CEM Explorer;    -   (xiii) compounds were purified by strong cation exchange (SCX)        chromatography using Isolute SPE flash SCX-2 or SCX-3 columns        (International Sorbent Technology Limited, Mid Glamorgan, UK);    -   (xiv) chiral preparative chromatography was carried out using        HPLC or SFC using a Waters SFC 100 or equivalent. A chiral        stationary phase such as a cellulose or amylose chiral Daicel        column or equivalent was chosen to optimise separation of        isomers within the sample. Semi preparative separations        typically used a chiral column with dimensions 30×250 mm, 5        micron with SFC flow rates of 100 ml/min or HPLC flow rate of 40        ml/min. Detection was by UV absorbance or mass spectrometric        detection. For UV detection a generic wavelength, typically 220        nm or 254 nm, was used or a wavelength was chosen to maximise        the product response. For mass detection, a soft ionization        technique such as electrospray ionization was employed allowing        the product to be detected by targeting MH+ response. Samples        were dissolved in a compatible solvent for injection into the        chromatographic system. For SFC separations, column temperature        was held constant at approximately 40° C. and back pressure        regulated to a constant pressure of approximately 100-150 bar.    -   (xv) chiral analysis was carried out using SFC or HPLC using a        Waters UPC2 SFC, Agilent 1200 HPLC or equivalent. A chiral        stationary phase such as a cellulose or amylose chiral Daicel        columns or equivalent was chosen to optimise separation of        isomers within the sample. Analytical separations typically used        a chiral column with dimensions 3.0×150 mm, 3 micron with SFC        flow rates of 2 ml/min or HPLC flow rates 0.5 ml/min. Detection        was by UV absorbance (DAD) and/or mass spectrometry (full scan).        The sample was dissolved in a compatible solvent at a        concentration of approximately 0.5 mg/ml and injected directly        into the chromatographic system. For SFC separations, column        temperature was held constant at approximately 40° C. and back        pressure regulated to a constant pressure of approximately        100-150 bar.    -   (xvi) in general Examples and intermediate compounds were named        using ACD Name. “Structure to Name” part of ChemDraw Ultra        (CambridgeSoft) or Biovia Draw 2016;    -   (xvii) where reactions refer to being degassed this can be        performed for example by purging the reaction solvent with a        constant flow of nitrogen for a suitable period of time (for        example 5 to 10 minutes)    -   (xviii) in addition to the ones mentioned above, the following        abbreviations have been used:

DMF N,N-dimethylformamide DMA N,N-dimethylacetamide DCM dichloromethaneTHF tetrahydrofuran conc. Concentrated m/z mass spectrometry peak(s)TBAF tetra n-butylammonium NMP 1-methylpyrrolidin-2-one fluoride EtOAcethyl acetate DIPEA N,N-diisopropylethylamine DME 1,2-dimethoxyethaneMeOH methanol MeCN acetonitrile MeOD d₄-methanol Et₂O diethyl ether DRU1,8-diazabi- cyclo[5.4.0]undec-7-ene AcOH acetic acid DCE1,2-dichloroethane Ac₂O acetic anhydride DMAP 4-dimethylaminopyridine hhour(s) EtOH ethanol MTBE methyl tert-butyl ether Sat. saturated rt roomtemperature fcc flash column chromatography NBS N-Bromosuccinimide FAFormic acid HATU 1-[Bis(dimethyl- SCX Strong cation exchangeamino)methylene]- 1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxidehexafluorophosphate SFC Supercritical fluid RuPhos dicyclohexyl(2′,6′-chromatography diisopropoxy- [1,1′-biphenyl]- 2-yl)phosphine DEADiethylamine

-   -   (xix) For XRPD analysis the instrument used was a Bruker D4. The        X-ray powder diffractogram was determined by mounting a sample        of the crystalline material on a Bruker single silicon crystal        (SSC) wafer mount and spreading out the sample into a thin layer        with the aid of a microscope slide. The sample was spun at 30        revolutions per minute (to improve counting statistics) and        irradiated with X-rays generated by a copper long-fine focus        tube operated at 40 kV and 40 mA with a wavelength of 1.5418        angstroms. The collimated X-ray source was passed through an        automatic variable divergence slit set at V20 and the reflected        radiation directed through a 5.89 mm anti scatter slit and a        9.55 mm detector slit. Samples were measured in reflection        geometry in θ-2θ configuration over the scan range 2° to 40° 2θ        with a nominal 0.12 second exposure per 0.02° increment. The        instrument was equipped with a Position sensitive detector        (Lynxeye). Persons skilled in the art of X-ray powder        diffraction will understand that the relative intensity of peaks        can be affected by, for example, grains above 30 microns in size        and non-unitary aspect ratios that may affect analysis of        samples. The skilled person will also understand that the        position of reflections can be affected by the precise height at        which the sample sits in the diffractometer and the zero        calibration of the diffractometer. The surface planarity of the        sample may also have a small effect. Hence the diffraction        pattern data presented are not to be taken as absolute values;    -   (xx) For the Differential Scanning Calorimetry the instrument        used was TA Instruments Q2000 DSC. Typically less than 3 mg of        material contained in a standard aluminium pan fitted with a lid        was heated over the temperature range 25° C. to 300° C. at a        constant heating rate of 10° C. per minute. A purge gas using        nitrogen was used—flow rate 50 mL per minute. Thermal data was        analysed using standard software, e.g., Universal v.4.5A from TA        INSTRUMENTS®.

Intermediate 1: (R)-tert-butyl 3-(bromomethyl)pyrrolidine-1-carboxylate

Triphenylphosphine (78 g, 298.1 mmol) was added portionwise to(R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (50 g, 248.4mmol) and CBr₄ (115 g, 347.8 mmol) in DCM (1 L) at 0° C. over a periodof 5 min. The reaction mixture was allowed to warm to it, and wasstirred at rt for 16 h, then was concentrated in vacuo and purified byfcc, eluting with 0-16% EtOAc in petroleum ether, to afford the titlecompound (61.6 g, 94%) as a colourless oil; ¹H NMR (300 MHz, CDCl₃) 1.47(9H, s), 1.72 (1H, dq), 1.99-2.16 (1H, m), 2.52-2.68 (1H, m), 3.10 (1H,dd), 3.26-3.44 (3H, m), 3.49 (1H, ddd), 3.59 (1H, dd).

Intermediate 2: (R)-tert-butyl3-(2-acetyl-3-oxobutyl)pyrrolidine-1-carboxylate

K₂CO₃ (48.3 g, 349.8 mmol) was added to (R)-tert-butyl3-(bromomethyl)pyrrolidine-1-carboxylate (61.6 g, 233.2 mmol) andpentane-2,4-dione (23.35 g, 233.2 mmol) in DMF (600 mL) at rt. Thereaction mixture was stirred at 80° C. for 16 h, then was allowed tocool to rt, diluted with EtOAc (500 mL), filtered and concentrated invacuo. The resulting crude product was purified by fcc, eluting with0-30% EtOAc in petroleum ether, to afford the title compound (43.9 g,66%) as a pale yellow oil; m/z MH⁺ 284.

Intermediate 3: (R)-tert-butyl3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine-1-carboxylate

3-Methyl-1H-1,2,4-triazol-5-amine (15.20 g, 154.9 mmol) was added in oneportion to (R)-tert-butyl3-(2-acetyl-3-oxobutyl)pyrrolidine-1-carboxylate (43.9 g, 154.9 mmol) inAcOH (500 mL) at rt. The reaction mixture was heated at 80° C. for 16 h,then was allowed to cool to it and concentrated in vacuo. The resultingcrude product was purified by flash C18 chromatography, eluting with5-80% MeOH in water, to afford the title compound (18.00 g, 34%) as apale yellow gum; ¹H NMR (300 MHz, CDCl₃) 1.45 (9H, s), 1.70 (1H, dt),1.91-2.07 (1H, m), 2.32-2.44 (1H, m), 2.60 (3H, s), 2.67 (3H, s), 2.78(5H, s), 3.06 (1H, dt), 3.23-3.54 (3H, dt); m/z MH⁺ 346.

Intermediate 4:(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine(Dihydrochloride Salt)

4 M HCl in 1,4-dioxane (200 ml, 800 mmol) was added to (R)-tert-butyl3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine-1-carboxylate(18 g, 52.11 mmol) in 1,4-dioxane (50 mL). The reaction mixture wasstirred at rt for 16 h. The resulting precipitate was collected byfiltration, washed with 1,4-dioxane (100 mL) and dried in vacuo toafford the title compound (13.80 g, 83%) as a white solid, which wasused without further purification; ¹H NMR (300 MHz, DMSO) 1.63 (1H, dq),1.90-2.05 (1H, m), 2.51 (4H, s), 2.65 (3H, s), 2.75-3.13 (7H, m), 3.26(2H, ddt), 7.30 (1H, br s) 9.28 (1H, s), 9.52 (1H, s); m/z MH⁺ 246.

Intermediate 4B (Free Base of Intermediate 4):(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine

1.25 M HCl in EtOH (36.4 mL, 45.51 mmol) was added in one portion to(R)-tert-butyl3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidine-1-carboxylate(2.62 g, 7.58 mmol) in EtOH (15 mL) at it. The resulting solution wasstirred at it for 5 days. The solvent was evaporated in vacuo to affordcrude HCl salt as an orange gum. The crude product was converted to thefree base using ion exchange chromatography, using an SCX column. Thedesired product was eluted from the column using 1 M NH₃/MeOH and purefractions were evaporated to dryness to afford the title compound (1.77g, 95%) as an orange gum; ¹H NMR (500 MHz, CDCl₃) 1.51 (1H, dq), 1.92(1H, ddd), 2.32 (1H, p), 2.60 (3H, s), 2.64 (1H, dd), 2.69 (3H, s), 2.80(3H, s), 2.82 (2H, dd), 2.98 (1H, dt), 3.03-3.13 (2H, m) NH notobserved; m/z MH⁺ 246.

Intermediate 5:(R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

DIPEA (4.39 mL, 25.14 mmol),(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (2 g, 6.28 mmol) and 5-bromo-2-fluoropyridine (1.66 g,9.43 mmol) were dissolved in n-propanol (10 mL) and sealed into amicrowave tube. The reaction mixture was heated at 150° C. for 2.5 h inthe microwave reactor and cooled to it. The solvent was removed underreduced pressure. The reaction mixture was poured into water (100 mL),extracted with EtOAc (3×100 mL), the organic layer was dried overNa₂SO₄, filtered and evaporated to afford a yellow solid.

The crude product was purified by crystallisation from EtOAc/petroleumether to afford the title compound (1.30 g, 52%) as a pale yellow solid;¹H NMR (300 MHz, CDCl₃) 1.90 (1H, dq), 2.19 (1H, dq), 2.63 (4H, s), 2.71(3H, s), 2.80 (3H, s), 2.93 (2H, qd), 3.24 (1H, dd), 3.45 (1H, q), 3.63(2H, q), 6.28 (1H, d), 7.54 (1H, dd), 8.19 (1H, d); m/z MH⁺ 401.

Intermediate 7: 1-((6-bromopyridin-3-yl)methyl)-4-methylpiperazine

6-Bromonicotinaldehyde (3 g, 16.13 mmol) and 1-methylpiperazine (4.85 g,48.39 mmol) were stirred in DCM (200 mL) at rt for 2 h. AcOH (0.097 g,1.61 mmol) and sodium triacetoxyborohydride (6.84 g, 32.26 mmol) wereadded and the mixture was stirred at rt for 16 h. The reaction mixturewas quenched with sat. aq. NaHCO₃ and the organic layer was separated.The aqeuous layer was extracted with EtOAc and the combined organiclayers were dried (Na₂SO₄), filtered and concentrated in vacuo. Theresulting crude product was purified by flash C18 chromatography,eluting with 0-80% MeOH in water, to afford the title compound (2.00 g,46%) as a yellow oil; ¹H NMR (300 MHz, DMSO) 2.55 (3H, s), 2.65 (4H, d),2.91 (4H, s), 3.49 (2H, s), 7.37-7.54 (2H, m), 8.27 (1H, d); m/z MH⁺270.

Intermediate 8: 1-((5-bromopyridin-2-yl)methyl)-4-methylpiperazine

5-Bromopicolinaldehyde (3.5 g, 18.82 mmol) and 1-methylpiperazine (5.65g, 56.45 mmol) in DCM (20 mL) was stirred at rt for 2 h. AcOH (0.113 g,1.88 mmol) and sodium triacetoxyborohydride (7.98 g, 37.63 mmol) wereadded and the reaction mixture was stirred at rt for 16 h. The reactionmixture was concentrated in vacuo and the resulting crude product waspurified by flash C18 chromatography, eluting with 0-100% MeOH in water,to afford the title compound (2.40 g, 47%) as a yellow oil; ¹H NMR (300MHz, DMSO) 2.26 (3H, s), 2.47 (8H, s), 3.58 (2H, s), 7.42 (1H, m), 8.03(1H, dd), 8.62 (1H, dd); m/z MH⁺ 270.

Intermediate 9: (6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)boronicacid

PdCl₂(dppf) (21.67 mg, 0.03 mmol) was added to1-((5-bromopyridin-2-yl)methyl)-4-methylpiperazine (160 mg, 0.59 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (165 mg,0.65 mmol) and potassium acetate (116 mg, 1.18 mmol) in 1,4-dioxane (4mL) at rt under nitrogen. The resulting mixture was stirred at 90° C.for 16 h.

The mixture was purified by flash C18-flash chromatography, elutiongradient 5 to 100% MeCN in water to afford impure title compound (80 mg,58%) as a yellow gum; m/z MH⁺ 236 (compound assumed to be boronic acidbased on LCMS data).

Intermediate 10:rac-6-((1-(5-bromopyrimidin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

DIPEA (0.878 mL, 5.03 mmol) was added to 5-bromo-2-chloropyrimidine (486mg, 2.51 mmol) andrac-2,5,7-trimethyl-6-(pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (800 mg, 2.51 mmol) (made in 4 steps in a similarfashion to Intermediate 4 starting from rac-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate), in EtOH (10 mL) at rt. Thereaction mixture was heated at 70° C. for 16 h, then was allowed to coolto rt and was concentrated in vacuo. The resulting crude product waspurified by fcc, eluting with 5-10% MeOH in DCM, to afford the titlecompound (350 mg, 35%) as a yellow solid; ¹H NMR (300 MHz, CDCl₃)1.79-1.93 (1H, m), 2.09-2.27 (1H, m), 2.49-2.62 (1H, m), 2.65 (3H, s),2.72 (3H, s), 2.80 (3H, s), 2.92 (2H, dd), 3.30 (1H, dd), 3.46-3.61 (1H,m), 3.64-3.81 (2H, m), 8.31 (2H, s); m/z MH⁺ 402.

Intermediate 11:(R)-2,5,7-trimethyl-6-((1-(pyridin-3-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (1.97 g, 6.03 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine(0.74 g, 3.02 mmol) and 3-iodopyridine (0.68 g, 3.32 mmol) in1,4-dioxane (10 mL). The reaction mixture was degassed and RuPhos 3rdgeneration precatalyst (0.25 g, 0.30 mmol) was added. The reactionmixture was heated at 90° C. for 5 h, then was allowed to cool to rt anddiluted with DCM and filtered. The filtrate was concentrated in vacuoand purified by fcc eluting with 0-5% 1 M NH₃/MeOH in DCM, to afford thetitle compound (0.413 g, 43%) as a yellow solid; ¹H NMR (500 MHz, CDCl₃)1.88 (1H, dq), 2.18 (1H, dtd), 2.58-2.67 (4H, m), 2.70 (3H, s), 2.78(3H, s), 2.89 (1H, dd), 2.93-3 (1H, m), 3.09 (1H, dd), 3.31-3.43 (2H,m), 3.49-3.56 (1H, m), 6.78 (1H, ddd), 7.11 (1H, ddd), 7.92-8 (2H, m);m/z MH⁺ 323.

Intermediate 12:(R)-6-((1-(6-bromopyridin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

NBS (229 mg, 1.28 mmol) was added in one portion to(R)-2,5,7-trimethyl-6-((1-(pyridin-3-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine(414 mg, 1.28 mmol) in MeCN (5 mL) at 0° C. under air. The reactionmixture was stirred at 0° C. and allowed to warm up slowly to rt over 3h. The resulting precipitate was isolated by filtration and washed withMeCN (5 mL) to afford the title compound (298 mg, 58%) as a white solid;¹H NMR (500 MHz, CDCl₃) 1.88 (1H, dq), 2.11-2.24 (1H, m), 2.61 (3H, s),2.62-2.67 (1H, m), 2.69 (3H, s), 2.78 (3H, s), 2.88 (1H, dd), 2.95 (1H,dd), 3.06 (1H, dd), 3.28-3.41 (2H, m), 3.48 (1H, td), 6.69 (1H, dd),7.25 (1H, dd), 7.69 (1H, d); m/z MH⁺ 401.

Intermediate 13: 3-chloro-6-(chloromethyl)pyridazine

1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (1.808 g, 7.78 mmol) wasadded in one portion to 3-chloro-6-methylpyridazine (2.00 g, 15.56 mmol)in DCE (100 mL) at rt. The reaction mixture was stirred at 60° C. for 2h, then was allowed to cool to rt and filtered. The filtrate wasconcentrated in vacuo, and was purified by fcc, eluting with 10-50%EtOAc in heptane, to afford the title compound (1.60 g, 63%) as a paleyellow oil; ¹H NMR (500 MHz, CDCl₃) 4.88 (2H, s), 7.58 (1H, d), 7.70(1H, d); m/z MH⁺ 163.

Intermediate 14: 4-((6-chloropyridazin-3-yl)methyl)morpholine

Morpholine (0.86 mL, 9.82 mmol) was added in one portion to3-chloro-6-(chloromethyl)pyridazine (1.6 g, 9.82 mmol) and DIPEA (2.05mL, 11.8 mmol) in THF (16 mL) at it. The reaction mixture was stirred atrt for 3 days, then was filtered and washed with THF. The combinedfiltrate was concentrated in vacuo and the resulting crude product waspurified by fcc, eluting with 0-5% MeOH in DCM, to afford the titlecompound (1.380 g, 66%) as a white solid; ¹H NMR (500 MHz, CDCl₃)2.47-2.56 (4H, m), 3.68-3.76 (4H, m), 3.85 (2H, s), 7.50 (1H, d), 7.68(1H, d); m/z MH⁺ 214.

Intermediate 15:(R)-2,5,7-trimethyl-6-((1-(pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (6.16 g, 18.91 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine(2.32 g, 9.46 mmol) and 5-bromopyrimidine (1.503 g, 9.46 mmol) in1,4-dioxane (64 mL). The reaction was degassed and RuPhos 3rd generationprecatalyst (0.395 g, 0.47 mmol) and RuPhos (0.221 g, 0.47 mmol) wereadded. The reaction mixture was stirred at 90° C. for 18 h. then wasallowed to cool to rt, diluted with DCM and filtered. The filtrate wasconcentrated in vacuo and purified by fcc eluting with 0-5% 1 M NH₃/MeOHin DCM, to afford the title compound (1.160 g, 38%) as a yellow solid;¹H NMR (500 MHz, CDCl₃) 1.88-1.95 (1H, m), 2.20 (1H, dtd), 2.61 (3H, s),2.63-2.68 (1H, m), 2.70 (3H, s), 2.80 (3H, s), 2.91 (1H, dd), 2.98 (1H,dd), 3.12 (1H, dd), 3.37 (1H, dt), 3.47 (1H, s), 3.54 (1H, td), 8.05(2H, s), 8.60 (1H, s); m/z MH⁺ 324.

Intermediate 16:(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-2,5,7-trimethyl-6-((1-(pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine(1.59 g, 4.92 mmol) was added to MeCN (80 mL) and the reaction mixturewas cooled to 0° C. NBS (1.050 g, 5.90 mmol) was then added in oneportion. The reaction mixture was allowed to warm to it and stirred for2 h. The resulting suspension was filtered and the impure solid wascollected and suspended in MeCN (10 mL) and heated at reflux. Thesuspension was allowed to cool to rt and the solid was collected byfiltration to afford the title compound (0.652 g, 33%) as a yellowsolid; ¹H NMR (500 MHz, CDCl₃) 1.90 (1H, dq), 2.16-2.25 (1H, m),2.58-2.67 (4H, m), 2.70 (3H, s), 2.80 (31, s), 2.88-2.94 (1H, m), 2.98(1H, dd), 3.10 (1H, dd), 3.34 (1H, dt), 3.44 (1H, dd), 3.51 (1H, td),7.87 (2H, s); m/z MH⁺ 402.

Intermediate 17:(S)-2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine

Potassium carbonate (2.43 g, 17.64 mmol) was added in one portion to2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.31g, 4.41 mmol) and (S)-1,3-dimethylpiperazine dihydrochloride (0.83 g,4.41 mmol) in MeCN (40 mL) at rt. The reaction mixture was stirred at80° C. for 18 h, then allowed to cool to it and filtered. The filtratewas concentrated in vacuo and the resulting crude product was purifiedby fcc, eluting with 0-10% 1 M NH₃/MeOH in DCM, to afford the tidecompound (506 mg, 35%) as a colourless oil; m/z MH⁺ 331.

Intermediate 18:3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

PdCl₂(dppf)-CH₂Cl₂ adduct (92 mg, 0.13 mmol) was added to4-bromo-3-methylbenzaldehyde (500 mg, 2.51 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (638 mg,2.51 mmol) and potassium acetate (493 mg, 5.02 mmol) in 1,4-dioxane (10mL) at rt. The reaction mixture was stirred at 90° C. for 16 h, then wasallowed to cool to it and was concentrate in vacuo. The resulting crudeproduct was purified by fcc, eluting with 10% EtOAc in petroleum ether,to afford the title compound (580 mg, 94%) as a yellow solid; ¹H NMR(400 MHz, CDCl₃) 1.39 (12H, s), 2.63 (3H, s), 7.64-7.70 (2H, m), 7.92(1H, d), 10.03 (1H, s); m/z MH⁺ 247.

Intermediate 19:(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl(benzaldehyde

Pd(Ph₃P)₄ (0.287 g, 0.25 mmol) was added to(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(1.00 g, 2.49 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.692 g,2.98 mmol) and 2 M sodium carbonate aq. solution (2.49 mL, 4.97 mmol) indegassed 1,4-dioxane (40 mL) and water (7.5 mL) at rt. The reactionmixture was stirred at 80° C. for 16 h, then allowed to cool to rt andconcentrated in vacuo. The resulting residue was taken up in DCM andpassed through a phase separating filter paper, then concentrated invacuo and purified by fcc, eluting with 0-10% MeOH in DCM, to afford thetitle compound (0.510 g, 48%) as a yellow solid; ¹H NMR (500 MHz, CDCl₃)1.88-1.96 (1H, m), 2.23 (1H, ddd), 2.62 (3H, s), 2.72 (4H, s), 2.81 (3H,s), 2.88-3.04 (2H, m), 3.20 (1H, dd), 3.45 (1H, dt), 3.54 (1H, dd), 3.63(1H, td), 7.9-7.99 (2H, m), 8.16 (2H, s), 8.42-8.53 (2H, m), 10.06 (1H,s); m/z MH⁺ 428.

Intermediate 20: tert-butyl4-(2-(dimethylamino)-2-oxoethyl)piperazine-1-carboxylate

HATU (3.74 g, 9.82 mmol) was added to2-(4-(tert-butoxycarbonyl)piperazin-1-yl)acetic acid (2 g, 8.19 mmol) inDMF (25 mL) at rt under air and the reaction mixture was stirred at rtfor 30 min. Dimethylamine (12.28 mL, 24.56 mmol) and DIPEA (4.29 mL,24.56 mmol) were added to the mixture at rt under air. The reactionmixture was stirred at it for 2 h and then poured into sat. aq. NaHCO₃(200 mL) and extracted with EtOAc (3×100 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting crude product was purified by flash C18 chromatography,eluting with 0-100% MeOH in water, to afford the title compound (1.65 g,74%) as a pale yellow solid; ¹H NMR (400 MHz, MeOD) 1.47 (9H, s), 2.49(4H, t), 2.95 (3H, s), 3.11 (3H, s), 3.27 (2H, s), 3.43-3.50 (4H, m);m/z MH⁺ 272.

Intermediate 21: N,N-dimethyl-2-(piperazin-1-yl)acetamidedihydrochloride

4 M HCl in EtOH (25 mL, 100 mmol) was added to tert-butyl4-(2-(dimethylamino)-2-oxoethyl)piperazine-1-carboxylate (1.6 g, 5.9mmol) in EtOH (25 mL) at it under air. The reaction mixture was stirredat rt for 2 h, then was concentrated in vacuo to afford the titlecompound (1.4 g, 100%) as a white solid; m/z MH⁺ 172.

Intermediate 22:2-(4-(4-bromobenzyl)piperazin-1-yl)-N,N-dimethylacetamide

N,N-dimethyl-2-(piperazin-1-yl)acetamide dihydrochloride (800 mg, 3.28mmol) was added to 4-bromobenzaldehyde (606 mg, 3.28 mmol) in THF (25mL) at rt under air and the reaction mixture was stirred at it for 3 h.Sodium triacetoxyborohydride (1389 mg, 6.55 mmol) and AcOH (2 drops)were added to the mixture and the reaction mixture was stirred at rt for16 h. The reaction mixture was diluted with water and concentrated invacuo to almost dryness. The crude product was purified by flash C18chromatography, eluting with 0-100% MeOH in water, to afford the titlecompound (704 mg, 63%) as a brown oil; ¹H NMR (400 MHz, CDCl₃) 2.49 (4H,m), 2.56 (4H, m), 2.95 (3H, s), 3.08 (3H, s), 3.18 (2H, s), 3.46 (2H,s), 7.17-7.25 (2H, m), 7.40-7.49 (2H, m); m/z MH⁺ 340

Intermediate 23: 2-(4-(4-bromobenzyl)piperazin-1-yl)ethanol

2-(Piperazin-1-yl)ethanol (1.407 g, 10.81 mmol) was added to4-bromobenzaldehyde (1 g, 5.40 mmol) in THF (25 mL) at rt and thereaction mixture was stirred at it for 1 h. Sodium triacetoxyborohydride(2.291 g, 10.81 mmol) and AcOH (2 drops) were added to the mixture at rtunder air and the reaction mixture was stirred at rt for 16 h, then waspoured into water (20 mL) and concentrated in vacuo to almost dryness.The resulting crude product was purified by flash C18 chromatography,eluting with 0-100% MeOH in water, to afford the title compound (1.20 g,74%) as a brown oil; ¹H NMR (400 MHz, CDCl₃) 2.23-2.57 (11H, m), 3.48(2H, s), 3.63 (2H, t), 7.22 (2H, d), 7.46 (2H, d); m/z MH⁺ 299.

Intermediate 24: 4-(4-(5-bromopyrimidin-2-yl)benzyl)morpholine

Pd(Ph₃P)₄ (578 mg, 0.50 mmol) was added to4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine(1516 mg, 5.00 mmol), 5-bromo-2-iodopyrimidine (1424 mg, 5 mmol) andNa₂CO₃ (1060 mg, 10.00 mmol) in toluene (20 mL) and water (4 mL), andthe reaction mixture was stirred at 120° C. for 3 days, then allowed tocool to rt and concentrated in vacuo. The residue was taken up in EtOAc(100 mL) and washed sequentially with water (2×20 mL). The organic layerwas isolated and dried over Na₂SO₄, filtered and concentrated in vacuo.The resulting crude product was purified by flash C18 chromatography,eluting with 5-50% MeOH in water, to afford the title compound (510 mg,31%) as a pale yellow solid; m/z MH⁺ 334.

Intermediate 25:(R)-2,5,7-trimethyl-6-((1-phenylpyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Degassed t-butanol (5 mL) was added to bromobenzene (74 μL, 0.7 mmol).(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (267 mg, 0.84 mmol), Cs₂CO₃ (1368 mg, 4.20 mmol), RuPhos(65 mg, 0.14 mmol) and RuPhos 3rd generation precatalyst (59 mg, 0.07mmol). The reaction mixture was heated at 90° C. overnight, then wasallowed to cool to rt and was concentrated in vacuo. The residue wasdissolved in DCM (30 mL) and washed with water (30 mL). The aqueouslayer was re-extracted with DCM (30 mL) and the combined organic layerswere passed through a hydrophobic (phase separation) frit andconcentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (72 mg, 32%) as a whitesolid; ¹H NMR (500 MHz, CDCl₃) 1.78-1.9 (1H, m), 2.1-2.21 (1H, m),2.55-2.64 (4H, m), 2.69 (3H, s), 2.78 (3H, s), 2.83-2.98 (2H, m), 3.08(1H, dd), 3.28-3.39 (2H, m), 3.45-3.55 (1H, m), 6.54 (2H, dd), 6.70 (1H,tt), 7.23 (2H, dd); m/z MH⁺ 322.

Intermediate 26:(R)-6-((1-(4-bromophenyl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

NBS (0.460 g, 2.58 mmol) was added to(R)-2,5,7-trimethyl-6-((1-phenylpyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine(0.83 g, 2.58 mmol) in THF (50 mL). The reaction mixture was stirred atrt for 2 h, then was concentrated in vacuo. The resulting crude productwas purified by flash C18 chromatography, eluting with 0-90% MeOH inwater, to afford the title compound (0.750 g, 73%) as a yellow solid;m/z MH⁺ 400.

Intermediate 27:(R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

PdCl₂(dppf)-CH₂Cl₂ adduct (94 mg, 0.11 mmol) was added to(R)-6-((1-(4-bromophenyl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(460 mg, 1.15 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (292 mg,1.15 mmol) and potassium acetate (226 mg, 2.30 mmol) in 1,4-dioxane (5mL) at rt. The reaction mixture was stirred at 90° C. for 16 h, then wasallowed to cool to rt and concentrated in vacuo. The resulting crudeproduct was purified by fcc, eluting with EtOAc, to afford the tidecompound (350 mg, 68%) as a pale yellow solid; m/z MH⁺ 448.

Intermediate 28: 2-bromo-5-((4-methylpiperazin-1-yl)methyl)pyrazine

Potassium iodide (0.659 g, 3.97 mmol) was added to 1-methylpiperazine(0.398 g, 3.97 mmol), 2-bromo-5-(bromomethyl)pyrazine (1 g, 3.97 mmol)and K₂CO₃ (0.549 g, 3.97 mmol) in DMF (30 mL) under air. The reactionmixture was stirred at rt for 4 h, then was concentrated in vacuo. Theresulting crude product was purified by flash C18 chromatography,eluting with 0-100% MeOH in water, to afford the tide compound (0.520 g,48%) as a yellow oil; m/z MH⁺ 271.

Intermediate 29: 5-bromo-2-((4-methylpiperazin-1-yl)methyl)pyrimidine

Potassium iodide (758 mg, 4.57 mmol) was added to5-bromo-2-(bromomethyl)pyrimidine (767 mg, 3.04 mmol),1-methylpiperazine (457 mg, 4.57 mmol) and K₂CO₃ (631 mg, 4.57 mmol) inDMF (15 mL). The reaction mixture was stirred at rt for 2 h, then wasconcentrated in vacuo. The resulting crude product was purified by flashC18 chromatography, eluting with 0-100% MeOH in water, to afford thetitle compound (340 mg, 41%) as a white solid; m/z MH⁺ 271.

Intermediate 30: 4-((6-bromopyridin-3-yl)methyl)morpholine

Potassium iodide (1.985 g, 11.96 mmol) was added to2-bromo-5-(bromomethyl)pyridine (3 g, 11.96 mmol), morpholine (1.042 g,11.96 mmol) and K₂CO₃ (1.652 g, 11.96 mmol) in DMF (25 mL), and thereaction mixture was stirred at it for 16 h, then was poured into water(150 mL) and extracted with EtOAc (3×50 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting crude product was purified by fcc, eluting with 0-75% EtOAc inpetroleum ether, to afford the title compound (2.60 g, 85%) as a whitesolid; ¹H NMR (400 MHz, CDCl₃) 2.41-2.48 (4H, m), 3.48 (2H, s),3.68-3.75 (4H, m), 7.46 (1H, d), 7.58 (1H, dd), 8.31 (1H, d); m/z MH⁺257.

Intermediate 31: 4-((6-(4-bromophenyl)pyridin-3-yl)methyl)morpholine

Pd(Ph₃P)₄ (0.674 g, 0.58 mmol) was added to4-((6-bromopyridin-3-yl)methyl)morpholine (1.5 g, 5.83 mmol),(4-bromophenyl)boronic acid (1.289 g, 6.42 mmol) and Na₂CO₃ (1.237 g,11.67 mmol) in 1,4-dioxane (14 mL) and water (7.00 mL) at rt. Thereaction mixture was stirred at 80° C. for 5 h, then was allowed to coolto it and concentrated in vacuo. The resulting crude product waspurified by fcc, eluting with 50% EtOAc in petroleum ether, to affordthe title compound (1.28 g, 66%) as a white solid; ¹H NMR (400 MHz,DMSO) 2.39 (4H, dd), 3.49-3.64 (6H, m), 7.58-7.76 (2H, m), 7.82 (1H,dd), 7.93-8.01 (1H, m), 8.01-8.09 (2H, m), 8.59 (1H, d); m/z MH⁺ 333.

Intermediate 32: 3-chloro-6-((4-methylpiperazin-1-yl)methyl)pyridazine

Potassium iodide (1.200 g, 7.23 mmol) was added to3-(bromomethyl)-6-chloropyridazine (1 g, 4.82 mmol), 1-methylpiperazine(0.724 g, 7.23 mmol) and K₂CO₃ (0.999 g, 7.23 mmol) in DMF (15 mL). Thereaction mixture was stirred at rt for 2 h, then was diluted with waterand the resulting solution was purified by flash C18 chromatography,eluting with 0-100% MeOH in water, to afford the title compound (300 mg,28%) as a white solid; ¹H NMR (300 MHz, DMSO) 2.19 (3H, s), 2.40 (8H,m), 3.77 (2H, s), 7.76 (1H, d), 7.88 (1H, d); m/z MH⁺ 227.

Intermediate 33: 2-(4-bromophenyl)-5-methylpyrimidine

Pd(Ph₃P)₄ (1.002 g, 0.87 mmol) was added to 2-bromo-5-methylpyrimidine(1.5 g, 8.67 mmol), (4-bromophenyl)boronic acid (1.74 g, 8.7 mmol) andNa₂CO₃ (1.84 g, 17.3 mmol) in 1,4-dioxane (35 mL) and water (7 mL) underair. The reaction mixture was stirred at 80° C. for 16 h, then wasallowed to cool to rt and concentrated in vacuo. The resulting crudeproduct was purified by fcc, eluting with 2-5% EtOAc in petroleum ether,to afford the title compound (1.00 g, 46%) as a yellow solid; ¹H NMR(300 MHz, CDCl₃) 2.37 (3H, s), 7.55 (2H, d), 8.30 (2H, d), 8.64 (2H, s);m/z MH⁺ 249.

Intermediate 34: 5-(bromomethyl)-2-(4-bromophenyl)pyrimidine

Benzoyl peroxide (58.3 mg, 0.24 mmol) was added to2-(4-bromophenyl)-5-methylpyrimidine (600 mg, 2.41 mmol) and NBS (429mg, 2.41 mmol) in CCl₄ (12 mL) under air. The reaction mixture wasstirred at 80° C. for 4 h, then was allowed to cool to rt andconcentrated in vacuo. The resulting crude product was purified by flashC18 chromatography, eluting with 5-100% MeOH in water, to afford thetitle compound (310 mg, 39%) as a yellow oil; m/z MH⁺ 327.

Intermediate 35:2-(4-bromophenyl)-5-((4-methylpiperazin-1-yl)methyl)pyrimidine

Potassium iodide (152 mg, 0.91 mmol) was added to5-(bromomethyl)-2-(4-bromophenyl)pyrimidine (300 mg, 0.91 mmol),1-methylpiperazine (82 mg, 0.82 mmol) and K₂CO₃ (126 mg, 0.91 mmol) inDMF (10 mL) under air. The resulting mixture was stirred at rt for 2 h.The solvent was removed in vacuo. The crude product was purified byflash C18 chromatography, eluting with 0-100% MeOH in water, to affordthe title compound (195 mg, 61%) as a yellow oil; ¹H NMR (300 MHz,CDCl₃) 2.61 (3H, s), 2.76-3.20 (8H, m), 3.61 (2H, s), 7.54 (2H, d), 8.33(2H, d), 8.73 (2H, s); m/z MH⁺ 347.

Intermediate 36: tert-butyl4-((6-bromopyridin-3-yl)methyl)piperazine-1-carboxylate

Sodium triacetoxyborohydride (4.56 g, 21.50 mmol) was added to6-bromonicotinaldehyde (2.00 g, 10.75 mmol), tert-butylpiperazine-1-carboxylate (4.01 g, 21.50 mmol) and AcOH (0.062 mL, 1.08mmol) in DCM (100 mL) at 20° C. The resulting solution was stirred at rtfor 2 h. The reaction mixture was washed with sat. NaHCO₃, passedthrough a phase separating filter paper and the solvent was removed invacuo. The crude product was purified by fcc, eluting with 0 to 70%EtOAc in heptane, to afford the title compound (2.80 g, 73.1%) as acolourless oil which crystallised on standing; ¹H NMR (500 MHz, CDCl₃)1.45 (9H, s), 2.31-2.43 (4H, m), 3.39-3.44 (4H, m), 3.47 (2H, s), 7.45(1H, dd), 7.55 (1H, dd), 8.29 (1H, dd); m/z MH⁺ 356

Intermediate 37: tert-butyl4-((6-(4-bromophenyl)pyridin-3-yl)methyl)piperazine-1-carboxylate

Pd(Ph₃P)₄ (0.389 g, 0.34 mmol) was added to tert-butyl4-((6-bromopyridin-3-yl)methyl)piperazine-1-carboxylate (2.40 g, 6.74mmol), (4-bromophenyl)boronic acid (1.35 g, 6.74 mmol) and potassiumcarbonate (2.79 g, 20.2 mmol) in degassed 1,4-dioxane (12 mL) and water(3 mL) at rt. The reaction mixture was heated at 85° C. in a microwavereactor for 3 h, then was allowed to cool to rt and diluted with EtOAc.The organic phase was passed through a phase separator and thenconcentrated in vacuo. The resulting crude product was purified by fcc,eluting with 0-5% MeOH in DCM, to afford the title compound (1.20 g,41%) as a yellow oil which solidified on standing: ¹H NMR (500 MHz,CDCl₃) 1.46 (9H, s), 2.36-2.47 (4H, m), 3.4-3.47 (4H, m), 3.55 (2H, s),7.56-7.62 (2H, m), 7.67 (1H, dd), 7.74 (1H, dd), 7.84-7.91 (2H, m),8.57-8.63 (1H, m); m/z MH⁺ 432

Intermediate 38: 4-((5-bromopyrimidin-2-yl)methyl)morpholine

Potassium iodide (758 mg, 4.57 mmol) was added to5-bromo-2-(bromomethyl)pyrimidine (767 mg, 3.04 mmol), morpholine (398mg, 4.57 mmol) and K₂CO₃ (631 mg, 4.57 mmol) in DMF (15 mL). Thereaction mixture was stirred at rt for 2 h, then was diluted with waterand concentrated in vacuo. The resulting crude product was purified byflash C18 chromatography, eluting with 0-100% MeOH in water, to affordthe title compound (720 mg, 92%) as a white solid; ¹H NMR (400 MHz,CDCl₃) 2.55-2.63 (4H, m) 3.74-3.82 (6H, m), 8.79 (2H, s); m/z MH⁺ 258

Intermediate 39: 4-((5-(4-bromophenyl)pyrimidin-2-yl)methyl)morpholine

Pd(Ph₃P)₄ (179 mg, 0.15 mmol) was added to4-((5-bromopyrimidin-2-yl)methyl)morpholine (400 mg, 1.55 mmol),(4-bromophenyl)boronic acid (311 mg, 1.55 mmol) and Na₂CO₃ (328 mg, 3.10mmol) in 1,4-dioxane (5 mL) and water (2.5 mL) at rt. The reactionmixture was stirred at 80° C. for 16 h, then was allowed to cool to itand concentrated in vacuo. The resulting crude product was purified byflash C18 chromatography, eluting with 0-100% MeOH in water, to affordthe title compound (330 mg, 64%) as a white solid; ¹H NMR (400 MHz,CDCl₃) 2.62-2.69 (4H, m), 3.78-3.86 (4H, m), 3.90 (2H, s), 7.42-7.53(2H, m), 7.63-7.74 (2H, m), 8.93 (2H, s); m/z MH⁺ 334.

Intermediate 40: 1-bromo-4-(bromomethyl)-2-methoxybenzene

Triphenylphosphine (5.53 ml, 23.9 mmol) was added portionwise to(4-bromo-3-methoxyphenyl)methanol (4.32 g, 20.0 mmol) and carbontetrabromide (7.26 g, 21.9 mmol) in DCM (100 ml) at 0° C. over a periodof 2 min. The reaction mixture was allowed to warm to it and was stirredat rt for 18 h, then was concentrated in vacuo. The resulting crudeproduct was purified by fcc, eluting with 0-50% DCM in heptane, toafford the title compound (5.57 g, 100%) as a colourless gum; ¹H NMR(400 MHz, CDCl₃) 3.91 (3H, s), 4.44 (2H, s), 6.86 (1H, dd), 6.92 (1H,d), 7.49 (1H, d).

Intermediate 41: 1-(4-bromo-3-methoxybenzyl)-4-methylpiperazine

Potassium iodide (2.135 g, 12.86 mmol) was added to1-bromo-4-(bromomethyl)-2-methoxybenzene (3 g, 10.7 mmol),1-methylpiperazine (1.29 g, 12.9 mmol) and K₂CO₃ (1.78 g, 12.9 mmol) inDMF (50 mL). The reaction mixture was stirred at rt for 16 h, then waspoured into water (200 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting crude product was purified by fcc,eluting with 0-5% MeOH in DCM, to afford the title compound (1.70 g,53%) as a pale yellow oil; ¹H NMR (400 MHz, CDCl₃) 2.34 (3H, s), 2.50(8H, br m), 3.48 (2H, s), 3.91 (3H, s), 6.82 (1H, dd), 6.91 (1H, d),7.46 (1H, dd); m/z MH⁺ 299.

Intermediate 42:(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid

PdCl₂(dppf)-CH₂Cl₂ adduct (0.464 g, 0.57 mmol) was added to1-(4-bromo-3-methoxybenzyl)-4-methylpiperazine (1.7 g, 5.68 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.89 g,11.4 mmol) and potassium acetate (1.67 g, 17.1 mmol) in 1,4-dioxane (25mL) at rt. The reaction mixture was stirred at 90° C. for 48 h, then wasallowed to cool to rt and concentrated in vacuo. The resulting crudeproduct was purified by flash C18 chromatography, eluting with 0-100%MeOH in water (with 0.5% NH₄HCO₃), to afford the title compound (1.10 g,73%) as a red solid; m/z MH⁺ 265.

Intermediate 43:(R)-6-((1-(6-chloropyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Triethylamine (2.10 mL, 15.1 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (1.2 g, 3.77 mmol) and 2,6-dichloropyrazine (0.562 g,3.77 mmol) in n-propanol (20 mL). The reaction mixture was stirred at90° C. for 16 h, then was allowed to cool to it and concentrate invacuo. Water (50 mL) was added to the residue and was extracted withEtOAc (3×50 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo. The resulting crude product waspurified by fcc, eluting with 0-5% MeOH in DCM, to afford the titlecompound (1.10 g, 82%) as a pale yellow solid; ¹H NMR (300 MHz, DMSO)1.81 (1H, dq), 2.07 (1H, m), 2.46 (3H, s), 2.62 (4H, s), 2.73 (3H, s),2.91 (2H, d), 3.18 (1H, m), 3.35 (1H, q), 3.61 (2H, td), 7.75 (1H, m),7.90 (1H, m); m/z MH⁺ 358.

Intermediate 44:(R)-2,5,7-trimethyl-6-((1-(6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph₃P)₄ (0.355 g, 0.31 mmol) was added to(R)-6-((1-(6-chloropyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(1.1 g, 3.07 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane in THF(50% wt) (1.54 g, 6.15 mmol) and Na₂CO₃ (1.30 g, 12.3 mmol) in1,4-dioxane (6 mL) and water (3 mL). The reaction mixture was stirred at80° C. for 16 h, then was allowed to cool to rt and concentrated invacuo. The resulting crude product was purified by fcc, eluting with1-5% MeOH in DCM, to afford the title compound (1.00 g, 96%) as a whitesolid; ¹H NMR (300 MHz, DMSO) 1.81 (1H, dq), 2.06 (1H, dq), 2.26 (3H,s), 2.54 (6H, d), 2.73 (3H, s), 2.92 (2H, m), 3.17 (1H, m), 3.36 (2H,m), 3.59 (2H, tt), 7.63 (1H, s), 7.73 (1H, s); m/z MH⁺ 338.

Intermediate 45:(R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

NBS (0.527 g, 2.96 mmol) was added to(R)-2,5,7-trimethyl-6-((1-(6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine(1 g, 2.96 mmol) in DCM (10 mL) at 0° C. under air. The reaction mixturewas stirred at 0° C. for 1 h, then water was added (25 mL) and themixture was extracted with DCM (3×25 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting crude product was purified by fcc, eluting with 1-2% MeOH inDCM, to afford the title compound (0.90 g, 73%) as a pale yellow solid;¹H NMR (300 MHz, DMSO) 1.81 (1H, dq), 2.06 (1H, dq), 2.39 (3H, s), 2.48(3H, s), 2.55 (1H, m), 2.62 (3H, s), 2.73 (3H, s), 2.92 (2H, m), 3.15(1H, m), 3.33 (1H, q), 3.58 (2H, ddd), 7.58 (1H, s); m/z MH⁺ 416.

Intermediate 46:(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

2,5-Dibromopyrazine (3.74 g, 15.7 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (5.00 g, 15.7 mmol) and DIPEA (13.7 mL, 78.6 mmol) inn-butanol (60 mL) at rt. The reaction mixture was heated at reflux for 2h, then was allowed to cool to rt and concentrated in vacuo. Theresulting crude product was triturated with water and filtered to affordthe title compound (4.86 g, 77%) as a cream solid; ¹H NMR (500 MHz,CDCl₃) 1.89 (1H, dq), 2.16-2.24 (1H, m), 2.61 (4H, s), 2.70 (3H, s),2.79 (3H, s), 2.93 (2H, tt), 3.23 (1H, dd), 3.45 (1H, dt), 3.6-3.68 (2H,m), 7.61 (1H, d), 8.10 (1H, d); m/z MH⁺ 402.

Intermediate 47:(R)-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)phenyl)methanol

(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (165 mg,0.71 mmol),(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(237 mg, 0.59 mmol) and Cs₂CO₃ (384 mg, 1.18 mmol) were added to1,4-dioxane (6.2 mL) and water (3.1 mL) and the reaction mixture wasdegassed for 10 minutes. XPhos 2^(nd) generation precatalyst (23 mg,0.03 mmol) was added and the reaction was stirred for 2 h at 90° C.,then allowed to cool to rt. The reaction mixture was diluted with EtOAc(50 mL). The organic layer was isolated and washed with sat. brine anddried over MgSO₄, filtered and concentrated in vacuo. The resultingcrude product was purified by fcc, eluting with 0-4% 1 M NH₃/MeOH inDCM, to afford the title compound (200 mg, 79%) as a white foam; ¹H NMR(500 MHz, CDCl₃) 1.74 (1H, t), 1.92 (1H, dq), 2.18-2.27 (1H, m), 2.62(4H, s), 2.71 (3H, s), 2.80 (3H, s), 2.87-3.02 (2H, m), 3.33 (1H, dd),3.55 (1H, dt), 3.68-3.8 (2H, m), 4.74 (2H, d), 7.41-7.47 (2H, m),7.84-7.91 (2H, m), 7.95 (1H, d), 8.51 (1H, d); m/z MH⁺ 430.

Intermediate 48:(R)-6-((1-(5-(4-(chloromethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)phenyl)methanol(200 mg, 0.47 mmol) was dissolved in DCM (7 mL) and DMF (0.34 mg, 4.66μmol). The reaction mixture was cooled to 0° C. and thionyl chloride(0.037 mL, 0.51 mmol) was added dropwise. The reaction mixture wasallowed to warm to it and was stirred at rt for 3 h, then was dilutedwith DCM (50 mL) and adjusted to pH 8-9 with Na₂CO₃ (2 M aq solution).The organic layer was isolated and washed with sat. brine, passedthrough a phase separating cartridge and concentrated in vacuo to affordthe title compound (181 mg, 87%) as a yellow solid which was usedwithout further purification; m/z MH⁺ 448.

Intermediate 49:(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde

Pd(Ph₃P)₄ (0.373 g, 0.32 mmol) was added to (4-formylphenyl)boronic acid(0.485 g, 3.23 mmol),(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(1.30 g, 3.23 mmol) and Na₂CO₃ (0.685 g, 6.46 mmol) in 1,4-dioxane (10mL) and water (2 mL). The reaction mixture was stirred at 80° C. for 16h, then allowed to cool to rt and concentrated in vacuo. The resultingcrude product was purified by flash C18 chromatography, eluting with5-80% MeOH in water, to afford the title compound (1.20 g, 87%) as ayellow solid; ¹H NMR (300 MHz, CDCl₃) 1.94 (1H, dq), 2.25 (1H, dq),2.57-3.07 (12H, m), 3.24-3.42 (1H, m), 3.45-3.87 (3H, m), 7.79-8.18 (5H,m), 8.60 (1H, d), 10.04 (1H, s); m/z MH⁺ 428.

Intermediate 50: 1-(4-bromo-2-methylbenzyl)-4-methylpiperazine

4-Bromo-2-methylbenzaldehyde (1 g, 5.02 mmol) and 1-methylpiperazine(0.503 g, 5.02 mmol) were combined with MeOH (20 mL) and the reactionmixture was stirred for 2 h at rt. NaCNBH₄ (0.631 g, 10.1 mmol) and AcOH(0.030 g, 0.50 mmol) were added and the reaction mixture was stirred atrt for 16 h, then concentrated in vacuo. The resulting crude product waspurified by flash C18 chromatography, eluting with 1-70% MeOH in water,to afford the title compound (1.00 g, 70%) as a yellow solid; m/z MH⁺283.

Intermediate 51:1-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine

PdCl₂(dppf)-CH₂Cl₂ adduct (0.058 g, 0.07 mmol) was added to1-(4-bromo-2-methylbenzyl)-4-methylpiperazine (0.2 g, 0.71 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.215 g,0.85 mmol) and potassium acetate (0.139 g, 1.41 mmol) in 1,4-dioxane (10mL) at rt. The reaction mixture was stirred at 80° C. for 16 h, then wasallowed to cool to rt and concentrated in vacuo. The resulting crudeproduct was purified by fcc, eluting with 0-50% EtOAc in petroleumether, to afford the title compound (70 mg, 30%) as a yellow solid; m/zMH⁺ 331.

Intermediate 52:1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)ethanone

Potassium carbonate (2.23 g, 16.2 mmol) was added in one portion to2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.4g, 8.08 mmol) and 1-(piperazin-1-yl)ethanone (1.04 g, 8.08 mmol) in MeCN(70 mL) at rt. The reaction mixture was stirred at 80° C. for 18 h, thenwas allowed to cool to rt and filtered. The filtrate was concentrated invacuo and the resulting crude product was purified by fcc, eluting with0-5% 1 M NH₃/MeOH in DCM, to afford the title compound (2.73 g, 98%) asa colourless oil; ¹H NMR (500 MHz, CDCl₃) 1.34 (12H, s), 2.07 (3H, s),2.41 (4H, dq), 3.42-3.46 (2H, m), 3.53 (2H, s), 3.59-3.64 (2H, m), 7.33(2H, d), 7.72-7.81 (2H, m); m/z MH⁺ 345.

Intermediate 53:(R)-6-((1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Triethylamine (1.75 mL, 12.6 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (1 g, 3.14 mmol), 3,6-dichloropyridazine (0.468 g, 3.14mmol) in n-propanol (10 mL) at rt under air. The reaction mixture wasstirred at 90° C. for 16 h, then allowed to cool to rt and partiallyconcentrated in vacuo. The precipitate was collected by filtration,washed with water (50 mL) and MeOH (10 mL) and dried in vacuo to affordthe title compound (0.610 g, 54%) as a brown solid, which was usedwithout further purification; ¹H NMR (400 MHz, DMSO) 1.85 (1H, dq), 2.11(1H, ddd), 2.48 (3H, s), 2.53-2.63 (1H, m), 2.64 (3H, s), 2.75 (3H, s),2.94 (2H, d), 3.14-3.23 (1H, m), 3.40 (1H, dt), 3.49-3.93 (2H, m), 7.00(1H, d), 7.47 (1H, d); m/z MH⁺ 358.

Intermediate 54: 2,4-dioxopentan-3-yl benzoate

Potassium hydroxide (50.5 g, 901 mmol) was added to benzoic acid (100 g,819 mmol) in DMF (1 L) at rt. The reaction mixture was stirred at 50° C.for 1 h. then 3-chloropentane-2,4-dione (110 g, 819 mmol) was added andreaction mixture was stirred at 50° C. overnight. The reaction mixturewas allowed to cool to rt, diluted with EtOAc (3 L), and washedsequentially with water (1 L×2), sat. aq. NH₄Cl (500 mL) and sat. brine(500 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The resulting crude product was purified by fcc,eluting with 0-20% EtOAc in petroleum ether, to afford the titlecompound (130 g, 72%) as a yellow oil; m/z MH⁺ 221.

Intermediate 55: 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-ylbenzoate

2,4-Dioxopentan-3-yl benzoate (58 g, 263 mmol) was added to3-methyl-1H-1,2,4-triazol-5-amine (27.1 g, 277 mmol) in AcOH (300 mL) atrt. The reaction mixture was stirred at 90° C. for 10 h. then wasallowed to cool to rt, concentrated in vacuo and adjusted to pH>7 withsat. aq. NaHCO₃. The mixture was extracted with EtOAc (3×500 mL). Thecombined organic layers were washed with sat. brine, passed through aphase separating filter paper and concentrated in vacuo to afford thetitle compound (52.0 g, 70%) as a beige solid; ¹H NMR (400 MHz, CDCl₃)2.57 (3H, s), 2.66 (3H, s), 2.70 (3H, s), 7.54-7.65 (2H, m), 7.71-7.80(1H, m), 8.24-8.31 (2H, m); m/z MH⁺ 283.

Intermediate 56: 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-ol

1 M aq. NaOH (177 mL, 177.11 mmol) was added to2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl benzoate (50 g, 177mmol) in EtOH (500 mL) at rt. The reaction mixture was stirred at rt for3 h, then partially concentrated in vacuo and the solution was slowlyacidified with 6 M aq. HCl until a precipitate formed (˜pH7). Theprecipitate was isolated by filtration, washed with water and dried invacuo to afford the title compound (24 g, 76%) as a cream solid; m/z MH⁺179.

Intermediate 57: tert-butyl(R)-3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate

Diisopropyl azodicarboxylate (52.4 mL, 269 mmol) was added dropwise to2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-ol (40 g, 224 mmol),tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate (46.2 g, 247 mmol) andtriphenylphosphine (70.7 g, 269 mmol) in THF (800 mL) at rt over aperiod of 2 h, and the reaction mixture was stirred at rt for 10 min andconcentrated in vacuo. The resulting crude product was purified by fcc,eluting with 0-100% EtOAc in petroleum ether, to afford the titlecompound (62.0 g, 80%) as a light yellow oil; ¹H NMR (400 MHz, DMSO)1.42 (9H, d), 2.07-2.14 (1H, m), 2.20-2.23 (1H, m), 2.47 (3H, s),2.51-2.54 (3H, m), 2.63 (3H, d), 3.34 (2H, s), 3.43-3.56 (2H, m), 4.74(1H, s); m/z MH⁺ 348.

Intermediate 58:(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride

4 M HCl in 1,4-dioxane (150 mL, 600 mmol) was added to tert-butyl(R)-3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidine-1-carboxylate(52 g, 149.7 mmol) in MeOH (200 mL) and the reaction mixture was stirredat rt for 2 h and then concentrated in vacuo. Acetone was added to theresidue and was stirred for 30 minutes. The precipitate was collected byfiltration to afford the title compound (26 g, 55%) as a white solid; ¹HNMR (400 MHz, DMSO) 2.03-2.13 (1H, m), 2.22-2.28 (1H, m), 2.51-2.54 (3H,m), 2.62 (3H, d), 2.74 (3H, s), 3.32-3.45 (3H, m), 3.46-3.56 (1H, m),4.90 (1H, s), 9.91 (2H, s); m/z MH⁺ 248.

Intermediate 58B (free base of Intermediate 58):(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (4.12 g, 16.7 mmol) was dissolved in MeOH and loadedonto a 50 g SCX column. The column was washed with MeOH then eluted with1 M NH₃ in MeOH. The solvent was removed in vacuo to afford the titlecompound (2.73 g, 66%) as an orange gum which was used in the next stepwithout purification; ¹H NMR (400 MHz, CDCl₃) 1.97-2.16 (2H, m), 2.60(3H, s), 2.65 (3H, s), 2.76 (3H, s), 3.08 (2H, ddd), 3.19 (1H, s),3.24-3.37 (2H, m), 4.62 (1H, ddt); m/z MH⁺ 248.

Intermediate 59:(R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

DIPEA (0.282 mL, 1.62 mmol) was added in one portion to5-bromo-2-fluoropyridine (0.166 mL, 1.62 mmol) and(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(400 mg, 1.62 mmol) in n-butanol (4 mL) at rt. The reaction mixture washeated at 150° C. in a microwave reactor for 2 h, then was allowed tocool to rt, diluted with EtOAc (50 mL), and washed sequentially withwater (20 mL) and sat. brine (20 mL). The organic layer was dried withMgSO₄, filtered and concentrated in vacuo. The resulting crude productwas purified by fcc, eluting with 0-5% MeOH in DCM, to afford the titlecompound (346 mg, 53%) as a yellow solid; m/z MH⁺ 403.

Intermediate 60:(R)-2,5,7-trimethyl-6-((1-(pyrimidin-5-yl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (1.98 g, 6.07 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(500 mg, 2.02 mmol) and 5-bromopyrimidine (321 mg, 2.02 mmol) in1,4-dioxane (20 mL). The reaction mixture was degassed and RuPhos 3rdgeneration precatalyst (169 mg, 0.20 mmol) and RuPhos (189 mg, 0.40mmol) were added. The resulting suspension was stirred at 90° C. for 18h, then allowed to cool to rt. The reaction mixture was diluted withEtOAc (50 mL) and was washed with water (30 mL) and sat. brine (25 mL).The organic layer was dried over MgSO₄, filtered and concentrated invacuo. The resulting crude product was purified by fcc, eluting with0-5% 1 M NH₃/MeOH in DCM, to afford the title compound (291 mg, 44%) asan orange gum, ¹H NMR (500 MHz, CDCl₃) 2.32 (1H, dtd), 2.46-2.55 (1H,m), 2.60 (3H, s), 2.62 (3H, s), 2.67 (3H, s), 3.5-3.62 (3H, m), 3.7-3.81(1H, m), 4.86 (1H, s), 8.12 (2H, s), 8.66 (1H, s); m/z MH⁺ 326

Intermediate 61:(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

NBS (159 mg, 0.89 mmol) was added portionwise to(R)-2,5,7-trimethyl-6-((1-(pyrimidin-5-yl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine(291 mg, 0.89 mmol) in MeCN (10 mL) at 0° C. over a period of 10 minunder air. The reaction mixture was stirred at 0° C. for 3 h. then wasdiluted with DCM (50 mL), and washed sequentially with water (20 mL) andsat. brine (20 mL). The organic layer was isolated and dried over MgSO₄,filtered and concentrated in vacuo. The resulting crude product waspurified by fcc, eluting with 0-4% 1 M NH₃/MeOH in DCM, to afford thetitle compound (140 mg, 39%) as a colourless gum; m/z MH⁺ 404.

Intermediate 62:(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

DIPEA (1.55 mL, 8.92 mmol) was added in one portion to2,5-dibromopyrazine (1.06 g, 4.46 mmol) and(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(735 mg, 2.97 mmol) in n-butanol (7 mL) at rt. The reaction mixture wasstirred at 120° C. for 16 h then allowed to cool to rt and concentratedin vacuo. The resulting crude product was purified by fcc, eluting with0-4% MeOH in DCM, to afford the title compound (740 mg, 62%) as a yellowfoam; ¹H NMR (500 MHz, CDCl₃) 2.33 (1H, dtd), 2.52 (1H, ddq), 2.60 (3H,s), 2.61 (3H, s), 2.65 (3H, s), 3.55 (1H, dd), 3.72 (1H, td), 3.75-3.88(2H, m), 4.81 (1H, tt), 7.70 (1H, d), 8.14 (1H, d); m/z MH⁺ 404.

Intermediate 63: 1-(4-Bromophenyl)-1,4-pentanedione

The title compound was synthesised according to reference Ryzhkov, I. O.et al Chemistry of Heterocyclic Compounds, 47(2), 182-193; 2011.

Intermediate 64: 3-(4-bromophenyl)-6-methylpyridazine

1-(4-Bromophenyl)-1,4-pentanedione (183 g, 0.717 mol) was dissolved inAcOH (1.8 L) and cooled to ° C. Hydrazine monohydrate (35 mL, 0.717 mol)was then added and the mixture was stirred for 30 min.2,3-Dichloro-5,6-dicyanobenzoquinone (244 g, 1.08 mol) was addedportionwise over 30 min and the reaction was stirred at rt for 40 min,then was concentrated in vacuo. The residue was partitioned betweenEtOAc (4 L) and sat. aq. NaHCO₃ (4 L). The organic layer was isolated,and the aqueous layer was extracted with EtOAc (2 L). The combinedorganic layers were washed with sat. aq. NaHCO₃ (10-2 L) and dried overMgSO₄, then concentrated in vacuo. The resulting crude product waspurified by suction column (4 L sinter, ˜half full of silica, 1 Lfractions, product loaded onto column by dissolving in DCM), elutingwith 40-60% EtOAc/petroleum ether. The resulting impure product wasstirred in diethyl ether (340 mL) for 30 min, then filtered and washedwith Et₂O (2×75 mL), then petroleum ether (2×75 mL) and air dried toafford the tide compound (91.2 g, 51%) as a beige solid; ¹H NMR (400MHz, CDCl₃) 2.75 (3H, s), 7.38 (1H, d), 7.65-7.60 (2H, m), 7.71 (1H, d),7.96-7.91 (2H, m); ¹³C NMR (400 MHz, CDCl₃) 22.1, 123.5, 124.4, 127.3,128.4, 132.2, 135.4, 156.2, 158.6.

Intermediate 65: 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine

1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (20.4 g, 87.8 mmol) wasadded portionwise to 3-(4-bromophenyl)-6-methylpyridazine (Intermediate64) (50 g, 200.7 mmol) in DCM (600 mL) at rt. The reaction mixture wasstirred at rt for 1 h then a further portion of1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (0.7 g) was added and thereaction mixture was stirred for 30 min, then morpholine (87 mL, 1003.6mmol) was added and the reaction mixture was stirred for 18 h. Thereaction mixture was diluted with 300 mL of water. The organic layer wasisolated and washed with water (300 mL) and concentrated in vacuo. Theresulting residue was slurried in refluxing EtOAc (150 mL), cooled to rtand filtered. The filtered solid was washed with 200 mL of MTBE anddried in vacuo to afford the title compound (53.4 g, 80%) as a whitesolid; ¹H NMR (400 MHz, CDCl₃) 2.56 (4H, m), 3.73 (4H, m), 3.91 (2H, s),7.64 (2H, m), 7.73 (1H, d), 7.81 (1H, d), 7.96 (2H, m); m/z MH⁺ 334.

Intermediate 66:8-((6-(4-bromophenyl)pyridazin-3-yl)methyl)-3-methyl-3,8-diazabicyclo[3.2.1]octane

Trichloroisocyanuric acid (65.3 mg, 0.28 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(200 mg, 0.80 mmol) in DCE (5.9 mL) at rt under air, and the reactionmixture was stirred at rt for 30 min. LCMS confirmed chloro intermediatehad been formed. 3-Methyl-3,8-diazabicyclo[3.2.1]octane (101 mg, 0.80mmol) was added and the reaction mixture was stirred at rt for 18 h. Thereaction mixture was diluted with DCM (50 mL), filtered and concentratedin vacuo. The resulting crude product was purified by fcc, eluting with0-10% 1 M NH₃/MeOH in DCM, to afford the title compound (193 mg, 64%) asa yellow solid; ¹H NMR (400 MHz, DMSO) 1.93 (2H, q), 2.12 (2H, dd), 2.32(3H, s), 2.37 (2H, d), 3.29 (2H, s), 4.01 (2H, s), 7.92-7.97 (2H, m),8.08 (1H, d), 8.29 (2H, d), 8.41 (1H, d), 2H missing assumed to be underDMSO peak; m/z MH⁺ 372

Intermediate 67:(R)-2-((6-(4-bromophenyl)pyridazin-3-yl)methyl)octahydropyrrolo[1,2-a]pyrazine

Trichloroisocyanuric acid (65.3 mg, 0.28 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(200 mg, 0.80 mmol) in DCE (5.2 mL) at rt under air. The reactionmixture was stirred at it for 30 min. LCMS confirmed chloro intermediatehad been formed. DIPEA (0.7 mL, 4.01 mmol) and(R)-octahydropyrrolo[1,2-a]pyrazine dihydrochloride (240 mg, 1.20 mmol)were added and the reaction mixture was stirred at it for 18 h, then wasdiluted with DCM (50 mL), filtered and concentrated in vacuo. Theresulting crude product was purified by fcc, eluting with 0-10% 1 MNH₃/MeOH in DCM to afford the title compound (189 mg, 63%) as a yellowsolid; ¹H NMR (400 MHz, DMSO) 1.19-1.31 (1H, m), 1.66 (3H, ddt),1.89-2.09 (3H, m), 2.14 (1H, td), 2.27 (1H, td), 2.73 (1H, d), 2.86-2.98(3H, m), 3.83-3.94 (2H, m), 7.74-7.8 (3H, m), 8.09-8.14 (2H, m), 8.23(1H, d); m/z MH⁺ 373.

Intermediate 68:(S)-2-((6-(4-bromophenyl)pyridazin-3-yl)methyl)octahydropyrrolo[1,2-a]pyrazine

Trichloroisocyanuric acid (65.3 mg, 0.28 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(200 mg, 0.80 mmol) in DCE (5.3 mL) at rt under air. The reactionmixture was stirred at it for 30 min. LCMS confirmed chloro had beenformed. DIPEA (0.6 mL, 3.21 mmol) and(S)-octahydropyrrolo[1,2-a]pyrazine hydrobromide (166 mg, 0.80 mmol)were added and the reaction mixture was stirred at rt for 3 days, thendiluted with DCM (50 mL), filtered and concentrated in vacuo. Theresulting crude product was purified by fcc, eluting with 0-10% 1 MNH₃/MeOH in DCM, to afford the title compound (299 mg, 100%) as a yellowsolid; m/z MH⁺ 373.

Intermediate 69:1-(4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one

Trichloroisocyanuric acid (65.3 mg, 0.28 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(200 mg, 0.80 mmol) in DCE (5.9 mL) at rt under air. The reactionmixture was stirred at rt for 30 min. A further 0.15 eq oftrichloroisocyanuric acid was added and the reaction mixture was stirredfor 30 min. 1-(Piperazin-1-yl)ethan-1-one (515 mg, 4.01 mmol) was addedand the reaction mixture was stirred at it for 18 h, then diluted withDCM (20 mL), filtered and concentrated in vacuo. The resulting crudeproduct was purified by fcc, eluting with 0-4% 1 M NH₃/MeOH in DCM toafford the title compound (246 mg, 82%) as a white solid; ¹H NMR (400MHz, CDCl₃) 2.09 (3H, s), 2.56 (4H, dt), 3.45-3.51 (2H, m), 3.62-3.68(2H, m), 3.94 (2H, s), 7.63-7.69 (2H, m), 7.71 (1H, d), 7.83 (1H, d),7.94-8.02 (2H, m); m/z MH⁺ 375.

Intermediate 70: 3-(4-bromophenyl)-6-(piperidin-1-ylmethyl)pyridazine

Trichloroisocyanuric acid (65.3 mg, 0.28 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(200 mg, 0.80 mmol) in DCE (5.5 mL) at rt under air. The reactionmixture was stirred at it for 30 min. A further 0.15 eq oftrichloroisocyanuric acid was added and the reaction mixture was stirredfor 30 min. Piperidine (397 μl, 4.01 mmol) was added and the reactionmixture was stirred at rt for 18 h., then diluted with DCM (20 mL),filtered and concentrated in vacuo. The resulting crude product waspurified by fee, eluting with 0-4% 1 M NH₃/MeOH in DCM, to afford thetitle compound (246 mg, 92%) as a white solid; ¹H NMR (400 MHz, DMSO)1.43 (2H, q), 1.54 (4H, p), 2.38-2.48 (4H, m), 3.81 (2H, s), 7.76-7.81(3H, m), 8.09-8.16 (2H, m), 8.23 (1H, d); m/z MH⁺ 332.

Intermediate 71:3-(4-bromophenyl)-6-((4-methylpiperazin-1-yl)methyl)pyridazine

Trichloroisocyanuric acid (65.3 mg, 0.28 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(200 mg, 0.80 mmol) in DCE (5.5 mL) at it under air. The reactionmixture was stirred at rt for 30 min. A further 0.15 eq oftrichloroisocyanuric acid was added and the reaction mixture was stirredfor 30 min. 1-Methylpiperazine (445 μl, 4.01 mmol) was added and thereaction mixture was stirred at it for 18 h, then was diluted with DCM(50 mL), filtered and concentrated in vacuo. The resulting crude productwas purified by fcc, eluting with 0-10% 1 M NH₃/MeOH in DCM, to affordthe title compound (237 mg, 85%) as a yellow solid; ¹H NMR (400 MHz,DMSO) 2.16 (3H, s), 2.28-2.4 (4H, m), 2.47 (4H, s), 3.83 (2H, s),7.74-7.8 (3H, m), 8.09-8.14 (2H, m), 8.23 (1H, d); m/z MH⁺ 347.

Intermediate 72:3-(4-bromophenyl)-6-((4-ethylpiperazin-1-yl)methyl)pyridazine

Trichloroisocyanuric acid (0.327 g, 1.40 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(1 g, 4.01 mmol) in DCE (27.0 mL) at rt under air. The reaction mixturewas stirred at rt for 30 min. 1-Ethylpiperazine (2.55 mL, 20.1 mmol) wasadded and the reaction mixture was stirred at rt for 18 h, then wasdiluted with DCM (20 mL), filtered and concentrated in vacuo. Theresulting crude product was purified by fcc, eluting with 0-10% 1 MNH₃/MeOH, to afford the title compound (125 mg, 9%) as a white solid; ¹HNMR (400 MHz, CDCl₃) 1.08 (3H, t), 2.42 (2H, q), 2.50 (4H, s), 2.62 (4H,s), 3.93 (2H, s), 7.63-7.68 (2H, m), 7.71 (1H, d), 7.80 (1H, d),7.94-8.00 (2H, m); m/z MH⁺ 361.

Intermediate 73:3-(4-bromophenyl)-6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazine

Trichloroisocyanuric acid (0.327 g, 1.40 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(1 g, 4.01 mmol) in DCE (26.5 mL) at rt under air. The reaction mixturewas stirred at rt for 30 min. 1-(2-Methoxyethyl)piperazine (2.98 mL,20.1 mmol) was added and the reaction mixture was stirred at rt for 18h, then was diluted with DCM (20 mL), filtered and concentrated invacuo. The resulting crude product was purified by fcc, eluting with0-10% 1 M NH₃/MeOH in DCM, to afford the tide compound (525 mg, 33%) asa white solid; ¹H NMR (400 MHz, CDCl₃) 2.61 (10H, dt), 3.35 (3H, s),3.5-3.55 (2H, m), 3.93 (2H, s), 7.62-7.67 (2H, m), 7.70 (1H, d), 7.80(1H, d), 7.94-8 (2H, m); m/z MH⁺ 391.

Intermediate 74:4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)-1,4-oxazepane

Trichloroisocyanuric acid (65.3 mg, 0.28 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(200 mg, 0.80 mmol) in DCE (5.9 mL) at rt under air. The reactionmixture was stirred at rt for 30 min. A further 0.15 eq oftrichloroisocyanuric acid was added and the reaction mixture was stirredfor 30 min. 1,4-Oxazepane (406 mg, 4.01 mmol) was added and the reactionmixture was stirred at rt for 18 h, then was diluted with DCM (50 mL),filtered and concentrated in vacuo. The resulting crude product waspurified by fcc, eluting with 0-4% 1 M NH₃/MeOH in DCM to afford thetitle compound (200 mg, 72%) as a yellow solid; ¹H NMR (400 MHz, DMSO)1.83 (2H, p), 2.72 (4H, q), 3.6-3.67 (2H, m), 3.72 (2H, t), 4.01 (2H,s), 7.73-7.81 (2H, m), 7.83 (1H, d), 8.07-8.16 (2H, m), 8.24 (1H, d);m/z MH⁺ 348.

Intermediate 75: 1-((6-(4-bromophenyl)pyridazin-3-yl)methyl)azepane

Trichloroisocyanuric acid (65.3 mg, 0.28 mmol) was added in one portionto a solution of 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)(200 mg, 0.80 mmol) in DCE (5.5 mL) at rt under air. The reactionmixture was stirred at rt for 30 min. A further 0.15 eq oftrichloroisocyanuric acid was added and the reaction mixture was stirredfor 30 min. Azepane (452 μl, 4.01 mmol) was added and the reactionmixture was stirred at rt for 3 days, then was diluted with DCM (50 mL),filtered and concentrated in vacuo. The resulting crude product waspurified by fcc, eluting with 0-4% 1 M NH₃/MeOH in DCM to afford thetitle compound (88 mg, 32%) as a yellow solid; ¹H NMR (400 MHz, DMSO)1.59 (8H, s), 2.64-2.7 (4H, m), 3.98 (2H, s), 7.74-7.79 (2H, m), 7.82(1H, d), 8.09-8.14 (2H, m) 8.23 (1H, d); m/z MH⁺ 346.

Intermediate 76: 4-((5-chloropyrazin-2-yl)methyl)morpholine

Sodium triacetoxyborohydride (4.46 g, 21.1 mmol) was added to5-chloropyrazine-2-carbaldehyde (1 g, 7.02 mmol) and morpholine (0.614mL, 7.02 mmol) in DCM (10 mL) at rt and the reaction mixture was stirredat rt for 4 h. The reaction mixture was diluted with sat. aq. NaHCO₃ andwas stirred for 10 min, then passed through a phase separating filterpaper and concentrated in vacuo to afford the title compound (1.180 g,79%) as a colourless oil; ¹H NMR (400 MHz, CDCl₃) 2.49-2.55 (4H, m),3.69 (2H, s), 3.71-3.77 (4H, m), 8.47 (1H, d), 8.55 (1H, d); m/z MH⁺214.

Intermediate 77: 4-((5-(4-bromophenyl)pyrazin-2-yl)methyl)morpholine

Pd(Ph₃P)₄ (135 mg, 0.12 mmol) was added in one portion to a degassedmixture of (4-bromophenyl)boronic acid (470 mg, 2.34 mmol),4-((5-chloropyrazin-2-yl)methyl)morpholine (500 mg, 2.34 mmol) and 2 Maq. Na₂CO₃ (2.34 mL, 4.68 mmol) in 1,4-dioxane (7.8 mL) and water (1.5mL) at rt. The reaction mixture was stirred at 80° C. for 2 h, then wasallowed to cool to rt, diluted with EtOAc (75 mL), and washedsequentially with water (20 mL) and sat. brine (20 mL). The organiclayer was dried over MgSO₄, filtered and concentrated in vacuo. Theresulting crude product was purified by fcc, eluting with 0-3% MeOH inDCM, to afford the title compound (730 mg, 93%) as a white solid; ¹H NMR(400 MHz, CDCl₃) 2.57 (4H, q), 3.72-3.79 (6H, m), 7.62-7.66 (2H, m),7.88-7.93 (2H, m), 8.71 (1H, d), 8.95 (1H, d); m/z MH⁺ 334.

Intermediate 78: 2-bromo-5-(pyrrolidin-1-ylmethyl)pyridine

Potassium iodide (331 mg, 1.99 mmol) was added to2-bromo-5-(bromomethyl)pyridine (500 mg, 1.99 mmol), pyrrolidine (142mg, 1.99 mmol) and K₂CO₃ (275 mg, 1.99 mmol) in DMF (10 mL). Thereaction mixture was stirred at rt for 16 h, then was diluted with water(50 mL), extracted with EtOAc (3×50 mL), and the combined organic layerswere washed with sat. brine (3×50 mL) and dried over Na₂SO₄, filteredand concentrated in vacuo to afford the title compound (470 mg, 98%) asa yellow oil; m/z MH⁺ 241.

Intermediate 79: 5-bromo-2-(bromomethyl)pyridine

Benzoyl peroxide (0.063 g, 0.26 mmol) was added to5-bromo-2-methylpyridine (0.9 g, 5.23 mmol), and NBS (0.978 g, 5.49mmol) in CCl₄ (10 mL) at 15° C. The reaction mixture was heated atreflux for 15 h, then was allowed to cool to rt. The reaction mixturewas diluted with DCM (100 mL), and washed sequentially with water (50mL), and sat. brine (50 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The resulting crude product waspurified by fcc, eluting with 5% EtOAc in petroleum ether, to afford thetitle compound (0.440 g, 34% if pure) as an impure purple oil; m/z MH⁺250.

Intermediate 80: 5-bromo-2-(pyrrolidin-1-ylmethyl)pyridine

Potassium iodide (437 mg, 2.63 mmol) was added to5-bromo-2-(bromomethyl)pyridine (660 mg, 2.63 mmol), pyrrolidine (187mg, 2.63 mmol) and K₂CO₃ (364 mg, 2.63 mmol) in DMF (10 mL). Thereaction mixture was stirred at rt for 16 h, then was quenched withwater (50 mL) and extracted with EtOAc (3×50 mL). The combined organiclayers were washed with sat. brine (3×50 mL) and dried over Na₂SO₄,filtered and concentrated in vacuo to afford the title compound (570 mg,90%) as a black oil; m/z MH⁺ 241.

Intermediate 81:(R)-3-methyl-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzaldehyde

XPhos palladium(II) biphenyl-2-amine chloride (20 mg, 0.02 mmol) wasadded to(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 16) (200 mg, 0.50 mmol),3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(Intermediate 18) (122 mg, 0.50 mmol) and Cs₂CO₃ (324 mg, 0.99 mmol) in1,4-dioxane (3 mL) and water (1.5 mL) at it. The reaction mixture wasstirred at 90° C. for 16 h, then allowed to cool to it and concentratedin vacuo. The resulting crude product was purified by flash C18chromatography, eluting with 5-100% MeCN in water, to afford the titlecompound (75 mg, 34%) as a yellow solid; ¹H NMR (400 MHz, CDCl₃) 1.90(1H, s), 2.27 (1H, s), 2.66 (7H, d), 2.77 (3H, s), 2.86 (3H, s),2.92-3.11 (2H, m), 3.24 (1H, s), 3.45-3.54 (1H, m), 3.59 (1H, s), 3.67(1H, s), 7.82 (2H, dt), 7.98 (1H, d), 8.24 (2H, s), 10.06 (1H, s); m/zMH⁺ 442.

Intermediate 82: (R)-tert-butyl4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridin-3-yl)methyl)piperazine-1-carboxylate

Degassed 1,4-dioxane (15 mL) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (Intermediate 4) (500 mg, 2.04 mmol) and tert-butyl4-((6-(4-bromophenyl)pyridin-3-yl)methyl)piperazine-1-carboxylate(Intermediate 37) (881 mg, 2.04 mmol). Cs₂CO₃ (1.99 g, 6.11 mmol) wasthen added followed by RuPhos (190 mg, 0.41 mmol) and RuPhos 3rdgeneration precatalyst (341 mg, 0.41 mmol). The reaction mixture washeated at 90° C. for 24 h, allowed to cool to rt and concentrated invacuo. The residue was taken up in DCM, filtered through Celite,concentrated in vacuo and purified by fcc, eluting with 0-10% MeOH inDCM, to afford the title compound (290 mg, 24%) as a beige solid; ¹H NMR(500 MHz, CDCl₃) 1.45 (9H, s), 1.82-1.94 (1H, m), 2.13-2.23 (1H, m),2.41 (4H, s), 2.62 (4H, s), 2.70 (3H, s), 2.78 (3H, s), 2.86-2.99 (2H,m), 3.14 (1H, dd), 3.37-3.47 (6H, m), 3.52 (2H, s), 3.57 (1H, td),6.58-6.64 (2H, m), 7.60 (1H, dd), 7.64 (1H, dd), 7.86-7.96 (2H, m), 8.51(1H, d); m/z MH⁺ 597.

Example 1:(R)-4-((6′-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)-[3,3′-bipyridin]-6-yl)methyl)morpholine

XPhos 2^(nd) generation precatalyst (29.4 mg, 0.04 mmol) was added to(R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 5) (150 mg, 0.37 mmol),(6-(morpholinomethyl)pyridin-3-yl)boronic acid (sourced commercially)(83 mg, 0.37 mmol) and Cs₂CO₃ (244 mg, 0.75 mmol) in 1,4-dioxane (2 mL)and water (1 mL). The reaction mixture was stirred at 80° C. for 3 h,then was allowed to cool to rt and concentrated in vacuo. The resultingcrude product was purified by preparative HPLC to afford the formic acidsalt of the title compound (80 mg, 36%) as a yellow solid; ¹H NMR (300MHz, MeOD) 1.89-2.08 (1H, m), 2.19-2.33 (1H, m), 2.56 (3H, s), 2.71-2.73(4H, m), 2.77-2.89 (7H, m), 3.04 (2H, d), 3.24-3.33 (1H, m), 3.44-3.57(1H, m), 3.57-3.75 (1H, m), 3.71-3.85 (5H, m), 3.98 (2H, d), 6.67 (1H,d), 7.58 (1H, d), 7.89 (1H, dd), 8.04 (1H, dd), 8.18 (2H, s, equates to2 equivalents of formate salt), 8.33 (1H, d), 8.76 (1H, d) m/z MH⁺ 499.

Example 4:(R)-2,5,7-trimethyl-6-((1-(6′-((4-methylpiperazin-1-yl)methyl)-[3,3′-bipyridin]-6-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph₃P)₄ (72.9 mg, 0.06 mmol) was added to(R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 5) (253 mg, 0.63 mmol),(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)boronic acid(Intermediate 9) (200 mg, 0.85 mmol) and Na₂CO₃ (134 mg, 1.26 mmol) intoluene (10 mL) and water (2 mL). The reaction mixture was stirred at80° C. for 16 h, allowed to cool to rt and concentrated in vacuo. Theresulting crude product was purified by preparative HPLC to afford theformic acid salt of the title compound (60 mg, 17%) as a yellow solid;¹H NMR (300 MHz, DMSO) 1.84 (1H, m), 2.10 (1H, m), 2.20 (3H, s),2.30-2.50 (12H, m), 2.63 (3H, s), 2.74 (3H, s), 2.92 (2H, d), 3.18 (1H,dd), 3.38 (1H, dt), 3.57 (4H, m), 6.55 (1H, d), 7.42 (1H, d), 7.84 (1H,dd), 7.96 (1H, dd), 8.20 (1H, s), 8.43 (1H, d), 8.72 (1H, dd); m/z MH⁺512.

Example 5:(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph₃P)₄ (17 mg, 0.01 mmol) was added to1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(sourced commercially) (95 mg, 0.30 mmol),(R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 5) (120 mg, 0.30 mmol) and Na₂CO₃ (63.4 mg, 0.60 mmol) in1,4-dioxane (3 mL) and water (1.5 mL) at rt. The reaction mixture wasstirred at 80° C. for 16 h, allowed to cool to rt and then concentratedin vacuo. The resulting crude product was purified by flash C18chromatography, eluting with 5-100% MeCN in water (+0.1% FA), to affordthe formic acid salt of the title compound (55 mg, 33%) as a whitesolid, ¹H NMR (400 MHz, MeOD) 1.99 (1H, dq), 2.26 (1H, dq), 2.57 (3H,s), 2.70 (1H, m), 2.85 (3H, s), 3.05 (6H, m), 3.25-3.34 (2H, m), 3.50(1H, m), 3.60 (1H, m), 3.70 (3H, m), 6.63 (1H, d), 7.42 (2H, d), 7.55(2H, d), 7.84 (1H, dd), 8.28 (1H, d), 8.47 (1H, s); m/z MH⁺ 511.

Example 6:(R)-4-(4-(2-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)benzyl)morpholine

XPhos 2^(nd) generation precatalyst (34 mg, 0.04 mmol) was added torac-6-((1-(5-bromopyrimidin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 10) (350 mg, 0.87 mmol),4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine(sourced commercially) (264 mg, 0.87 mmol) and Cs₂CO₃ (567 mg, 1.74mmol) in 1,4-dioxane (3 mL) and water (1.5 mL) at rt. The reactionmixture was stirred at 80° C. for 16 h, then was allowed to cool to rtand was concentrated in vacuo. The resulting crude product was purifiedby flash C18 chromatography, eluting with 5-100% MeCN in water (+0.08%NH₄CO₃). The resulting racemic product (390 mg) was separated bypreparative chiral-HPLC on a Chiralpak IA column, eluting with 50% EtOHin TBME (modified with DEA) as eluent, to afford the title compound (120mg, 31%) as a white solid; ¹H NMR (400 MHz, MeOD) 1.90-2.04 (1H, m),2.23 (1H, dt), 2.50 (4H, t), 2.57 (3H, s), 2.74 (4H, s), 2.86 (3H, s),3.05 (2H, d), 3.39 (1H, dd), 3.60 (3H, d), 3.68-3.79 (5H, m), 3.86 (1H,ddd), 7.45 (2H, d), 7.55 (2H, d), 8.61 (2H, s); m/z MH⁺ 499.

Example 7:(R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyridin-2-yl)pyrazin-2-yl)methyl)morpholine

Pd(Ph₃P)₄ (46.1 mg, 0.04 mmol) was added to4-((5-chloropyrazin-2-yl)methyl)morpholine (Intermediate 76) (85 mg,0.40 mmol),(R)-6-((1-(6-bromopyridin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 12) (160 mg, 0.40 mmol) and1,1,1,2,2,2-hexamethyldistannane (131 mg, 0.40 mmol) in 1,4-dioxane (5mL) at rt. The reaction mixture was stirred at 110° C. for 16 h, thenallowed to cool to rt and concentrated in vacuo. The resulting crudeproduct was purified by flash C18 chromatography, eluting with 5-100%MeCN in water (+0.1% FA), to afford the title compound (87 mg, 43%) as ayellow solid; ¹H NMR (300 MHz, MeOD) 1.89-2.08 (1H, m), 2.18-2.31 (1H,m), 2.56 (3H, s), 2.60-2.87 (10H, m), 3.05 (2H, dd), 3.23 (1H, dd),3.37-3.85 (10H, m) 7.10 (1H, dd), 8.03 (1H, d), 8.20 (1H, d), 8.66 (1H,d), 9.31 (1H, d); m/z MH⁺ 500.

Example 8:(R)-2,5,7-trimethyl-6-((1-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph₃P)₄ (202 mg, 0.17 mmol) was added to(R)-6-((1-(6-bromopyridin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 12) (700 mg, 1.74 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(sourced commercially) (607 mg, 1.92 mmol) and 1 M aq. Na₂CO₃ (3.49 mL,3.49 mmol) in degassed 1,4-dioxane (7 mL) at rt. The reaction mixturewas stirred at 80° C. for 18 h, then allowed to cool to rt andconcentrated in vacuo. The residue was taken up in DCM, filtered and theresulting crude product was purified by fcc, eluting with 0-10% 1 MNH₃/MeOH in DCM, then further purified by recrystallization from EtOAc(with a small amount of MeOH), to afford the title compound (240 mg,27%) as a pale yellow crystalline solid; ¹H NMR (500 MHz, CDCl₃)1.86-1.94 (1H, m), 2.14-2.23 (1H, m), 2.28 (3H, s), 2.49 (8H, s), 2.62(4H, s), 2.71 (3H, s), 2.79 (3H, s), 2.86-3.01 (2H, m), 3.14 (1H, dd),3.37-3.48 (2H, m), 3.54 (2H, s), 3.55-3.61 (1H, m), 6.86 (1H, dd), 7.37(2H, d), 7.59 (1H, dd), 7.82-7.88 (2H, m), 8.06 (1H, d); m/z MH⁺ 511.

Example 9:(R)-4-((6-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyridin-2-yl)pyridazin-3-yl)methyl)morpholine

Pd(Ph₃P)₄ (343 mg, 0.30 mmol) was added in one portion to4-((6-chloropyridazin-3-yl)methyl)morpholine (Intermediate 14) (634 mg,2.97 mmol),(R)-6-((1-(6-bromopyridin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 12) (1.19 g, 2.97 mmol) and1,1,1,2,2,2-hexamethyldistannane (0.615 mL, 2.97 mmol) in 1,4-dioxane(30 mL) at rt. The reaction mixture was stirred at 100° C. for 20 h,then allowed to cool to rt, filtered and washed with DCM (20 mL). Thefiltrate was concentrated in vacuo and the resulting crude product waspurified by fcc, eluting with 0-10% 1 M NH₃/MeOH in DCM, then furtherpurified by preparative HPLC, then dissolved in MeOH and loaded onto a50 g SCX column. The column was washed with MeOH (2× column volumes)then eluted with 1 M NH₃/MeOH. The resulting gum was triturated withEt₂O to give a solid which was filtered and dried in vacuo to afford thetitle compound (608 mg, 41%) as a pale yellow solid; ¹H NMR (500 MHz,DMSO) 1.87 (1H, dq), 2.06-2.22 (1H, m), 2.45 (7H, d), 2.64 (4H, s), 2.74(3H, s), 2.93 (2H, d), 3.12 (1H, dd), 3.33-3.38 (1H, m), 3.48 (1H, dd),3.51-3.64 (5H, m), 3.79 (2H, s), 7.06 (1H, dd), 7.71 (1H, d), 8.05 (1H,d), 8.33 (2H, dd); m/z MH⁺ 500.

Example 10:6-(((R)-1-(2-(4-(((S)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 16) (300 mg, 0.75 mmol),(S)-2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(Intermediate 17) (296 mg, 0.89 mmol), Pd(Ph₃P)₄ (86 mg, 0.07 mmol) andpotassium carbonate (206 mg, 1.49 mmol) were dissolved in 1,4-dioxane(12 mL) and water (4 mL) and heated at 80° C. for 18 h. The reactionmixture allowed to cool to rt, then poured into DCM (50 mL). The aqueouslayer was separated then extracted with 20% MeOH/DCM. The combinedorganic layers were dried over MgSO₄, filtered and concentrated invacuo. The resulting crude product was purified by fcc, eluting with0-5% 1 M NH₃/MeOH in DCM. The resulting gum was triturated with EtOAcand the resulting solid was filtered and dried in vacuo to afford thetitle compound (52 mg, 13%) as a white solid; ¹H NMR (500 MHz, DMSO)1.06 (3H, d), 1.78-1.9 (2H, m), 1.98 (1H, d), 2.10 (5H, s), 2.41 (1H,s), 2.47 (4H, s), 2.55 (2H, d), 2.64 (4H, s), 2.74 (3H, s), 2.92 (2H,d), 3.04-3.18 (2H, m), 3.34 (1H, d), 3.46 (1H, dd), 3.5-3.58 (1H, m),3.97 (1H, d), 7.33 (2H, d), 8.16 (2H, d), 8.20 (2H, s); m/z MH⁺ 526.

Example 11:(R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-yl)methyl)morpholine

XPhos 2^(nd) generation precatalyst (9 mg, 0.01 mmol) was added to(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 16) (90 mg, 0.22 mmol),(6-(morpholinomethyl)pyridin-3-yl)boronic acid (sourced commercially)(50 mg, 0.22 mmol) and Cs₂CO₃ (146 mg, 0.45 mmol) in 1,4-dioxane (3 mL)and water (1.5 mL) at rt. The reaction mixture was stirred at 90° C. for16 h, then allowed to cool to rt and concentrated in vacuo. Theresulting crude product was purified by flash C18 chromatography,eluting with 5-100% MeCN in water, to afford the title compound (22 mg,20%) as a white solid; ¹H NMR (400 MHz, MeOD) 2.00 (1H, dq), 2.26 (1H,dq), 2.57 (3H, s), 2.64 (4H, s), 2.75 (4H, s), 2.86 (3H, s), 3.08 (2H,h), 3.25 (1H, dd), 3.46 (1H, dt), 3.54-3.72 (2H, m), 3.72-3.83 (6H, m),7.63 (1H, d), 8.24 (2H, s), 8.61 (1H, dd), 9.34 (1H, d); m/z MH⁺ 500.

Example 12:(R)-6-((1-(2-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

XPhos 2^(nd) generation precatalyst (20 mg, 0.02 mmol) was added to(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 16) (200 mg, 0.50 mmol),(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid(Intermediate 42) (131 mg, 0.50 mmol) and Cs₂CO₃ (324 mg, 0.99 mmol) in1,4-dioxane (3 mL) and water (1.5 mL) at rt. The reaction mixture wasstirred at 90° C. for 16 h, allowed to cool to rt and concentrated invacuo. The resulting crude product was purified by flash C18chromatography, eluting with 5-100% MeCN in water, to afford the formicacid salt of the title compound (56 mg, 19%) as a pale yellow solid; ¹HNMR (400 MHz, MeOD) 2.00 (1H, dq), 2.25 (1H, ddd), 2.57 (3H, s), 2.72(10H, m), 2.87 (3H, s), 2.99-3.15 (7H, m), 3.22 (1H, dd), 3.44 (1H, dt),3.51-3.72 (4H, m), 3.83 (3H, s), 7.04 (1H, dd), 7.14 (1H, d), 7.49 (1H,d), 8.19 (2H, s), 8.49 (1H, s); m/z MH⁺ 542.

Example 13:(R)-2,5,7-trimethyl-6-((1-(2-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

1-Methylpiperazine (34 mg, 0.34 mmol) was added to(R)-3-methyl-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzaldehyde(75 mg, 0.17 mmol) in DCM (0.5 mL) at rt under air and the reactionmixture was stirred for 2 h. Sodium triacetoxyborohydride (180 mg, 0.85mmol) was added and the reaction mixture was stirred at rt for 50 h,then was concentrated in vacuo. The resulting crude product was purifiedby flash C18 chromatography, eluting with 5-100% MeCN in water, toafford the title compound (60 mg, 67%) as a yellow solid; ¹H NMR (400MHz, MeOD) 2.00 (1 dq), 2.26 (1H, ddd), 2.42 (3H, s), 2.57 (3H, s), 2.72(10H, m), 2.87 (3H, s), 3.06 (7H, m), 3.23 (1H, dd), 3.44 (1H, dt),3.52-3.70 (4H, m), 7.24-7.32 (2H, m), 7.54 (1H, d), 8.23 (2H, s); m/zMH⁺ 526.

Example 14:6-(((R)-1-(2-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzaldehyde(Intermediate 19) (120 mg, 0.28 mmol) was added to(2R,6S)-2,6-dimethylpiperazine (sourced commercially) (32 mg, 0.28 mmol)in DCM (3 mL), and the reaction mixture was stirred at rt for 2 h. AcOH(1.607 μl, 0.03 mmol) and sodium triacetoxyborohydride (178 mg, 0.84mmol) were added and the reaction mixture was stirred for 2 h, then wasconcentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (16 mg, 11%) as a whitesolid; ¹H NMR (300 MHz, MeOD) 1.18 (6H, s), 1.94 (3H, ddd), 2.21 (1H,m), 2.56 (3H, s), 2.73 (4H, m), 2.84 (3H, s), 3.08 (4H, m), 3.18 (3H,m), 3.58 (2H, m), 3.62 (4H, m), 7.41 (2H, dd), 8.17 (4H, dt); m/z MH⁺526.

Example 15:(R)—N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)acetamide

PdCl₂(dppf)-CH₂Cl₂ adduct (168 mg, 0.21 mmol) was added to2-(4-(4-bromobenzyl)piperazin-1-yl)-N,N-dimethylacetamide (Intermediate22) (700 mg, 2.06 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (627 mg,2.47 mmol) and potassium acetate (404 mg, 4.11 mmol) in 1,4-dioxane (10mL) at rt. The reaction mixture was stirred at 80° C. for 16 h, thenallowed to cool to rt and concentrated in vacuo. The resulting crudeproduct was purified by flash C18 chromatography, eluting with 0-100%MeOH in water, to afford(4-((4-(2-(dimethylamino)-2-oxoethyl)piperazin-1-yl)methyl)phenyl)boronic acid (186 mg, 30%) that was used directly withoutcharacterisation. Pd(Ph₃P)₄ (31.6 mg, 0.03 mmol) was added to(4-((4-(2-(dimethylamino)-2-oxoethyl)piperazin-1-yl)methyl)phenyl)boronicacid (92 mg, 0.30 mmol),(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 16) (110 mg, 0.27 mmol) and Na₂CO₃ (58.0 mg, 0.55 mmol) in1,4-dioxane (2 mL) and water (1 mL) at rt. The reaction mixture wasstirred at 80° C. for 16 h, then was allowed to cool to rt andconcentrated in vacuo. The resulting crude product was purified by flashC18 chromatography, eluting with 0-100% MeCN in water (+0.1% FA), thenfurther purified by preparative HPLC to afford the title compound (50mg, 31%) as a white solid; ¹H NMR (300 MHz, MeOD) 1.98 (1H, dt),2.16-2.34 (1H, m), 2.43-2.64 (10H, m), 2.73 (4H, s), 2.84 (3H, s), 2.93(3H, s), 2.97-3.15 (5H, m), 3.22 (3H, d), 3.33-3.49 (2H, m), 3.48-3.70(4H, m), 7.41 (2H, d), 8.11-8.21 (4H, m); m/z MH⁺ 583.

Example 16:(R)-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethanol

PdCl₂(dppf)-CH₂Cl₂ adduct (164 mg, 0.20 mmol) was added to2-(4-(4-bromobenzyl)piperazin-1-yl)ethanol (Intermediate 23) (600 mg,2.01 mmol), 4,4,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(611 mg, 2.41 mmol) and potassium acetate (394 mg, 4.01 mmol) in1,4-dioxane (10 mL) at rt. The reaction mixture was stirred at 80° C.for 16 h, then was allowed to cool to rt and concentrated in vacuo. Theresulting crude product was purified by flash C18 chromatography,eluting with 0-100% MeOH in water, to afford(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)boronic acid (143mg, 27%) as a brown solid that was used directly withoutcharacterisation. Pd(Ph₃P)₄ (31.6 mg, 0.03 mmol) was added to(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)boronic acid (87 mg,0.33 mmol),(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 16) (110 mg, 0.27 mmol) and Na₂CO₃ (58.0 mg, 0.55 mmol) in1,4-dioxane (2 mL) and water (1 mL) at rt. The reaction mixture wasstirred at 80° C. for 16 h, then was allowed to cool to rt andconcentrated in vacuo. The resulting crude product was purified by flashC18 chromatography, eluting with 0-100% MeCN in water (+0.1% FA), thenfurther purified by preparative HPLC to afford the title compound (50mg, 34%) as a white solid; ¹H NMR (300 MHz, CDCl₃) 1.88-2.02 (1H, m),2.15-2.26 (1H, m), 2.68 (18H, m), 2.82 (3H, s), 2.87-3.05 (2H, m), 3.18(1H, dd), 3.36-3.58 (2H, m), 3.58-3.71 (5H, m), 7.41 (2H, d), 8.14 (2H,s), 8.21-8.30 (2H, m); m/z MH⁺ 542.

Example 17:(R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethanone

Pd(Ph₃P)₄ (28.7 mg, 0.02 mmol) was added to1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)ethanone(Intermediate 52) (86 mg, 0.25 mmol),(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 16) (100 mg, 0.25 mmol) and Na₂CO₃ (53 mg, 0.50 mmol) in1,4-dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at80° C. for 16 h, then allowed to cool to rt and concentrated in vacuo.The resulting crude product was purified by preparative HPLC to affordthe title compound (50 mg, 37%) as a yellow solid; ¹H NMR (300 MHz,MeOD) 1.96 (1H, dq), 2.10 (3H, s), 2.22 (1H, m), 2.64 (11H, m), 2.84(3H, s), 3.03 (2H, dd), 3.20 (1H, dd), 3.60 (9H, m), 7.43 (2H, m), 8.19(4H, d); m/z MH⁺ 540.

Example 18:(R)-6-((1-(2-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Sodium triacetoxyborohydride (283 mg, 1.33 mmol) was added to(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzaldehyde(Intermediate 19) (190 mg, 0.44 mmol) and 1-(2-methoxyethyl)piperazine(77 mg, 0.53 mmol) and AcOH (0.013 mL, 0.22 mmol) in DCM (20 mL) at rt.The reaction mixture was stirred at rt for 4 h, then was concentrated invacuo, neutralised with 1 M NH₃/MeOH and concentrated in vacuo. Theresulting residue was taken up in DCM, filtered and purified by fcc,eluting with 0-5% 1 M NH₃/MeOH in DCM, to afford the title compound (175mg, 71%) as a pale yellow solid; ¹H NMR (500 MHz, CDCl₃) 1.86-1.96 (1H,m), 2.14-2.25 (1H, m), 2.39-2.6 (10H, m), 2.62 (3H, s), 2.64-2.69 (1H,m), 2.71 (3H, s), 2.80 (3H, s), 2.87-3.02 (2H, m), 3.17 (1H, dd), 3.34(3H, s), 3.39-3.46 (1H, m), 3.47-3.53 (3H, m), 3.56 (2H, s), 3.59 (1H,td), 7.39 (2H, d), 8.13 (2H, s), 8.23 (2H, d); mm/z MH⁺ 556.

Example 19:(R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)morpholine

RuPhos 3rd generation precatalyst (50 mg, 0.06 mmol) was added to4-(4-(5-bromopyrimidin-2-yl)benzyl)morpholine (Intermediate 24) (200 mg,0.60 mmol),(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine·2HCl(Intermediate 4) (190 mg, 0.60 mmol), Cs₂CO₃ (780 mg, 2.39 mmol) andRuPhos (55.8 mg, 0.12 mmol) in 1,4-dioxane (8 mL) at rt. The reactionmixture was stirred at 90° C. for 6 h, allowed to cool to rt andconcentrated in vacuo. The resulting crude product was purified by flashC18 chromatography, eluting with 0-100% MeOH in water (+0.1% FA), toafford the title compound (180 mg, 60%) as a yellow solid; ¹H NMR (300MHz, MeOD) 1.87-2.06 (1H, m), 2.16-2.27 (1H, m), 2.53-2.62 (7H, m), 2.73(4H, s), 2.84 (3H, s), 3.04 (2H, dd), 3.20 (1H, dd), 3.41 (1H, dt),3.49-3.71 (4H, m), 3.71-3.77 (4H, m), 7.43 (2H, d), 8.13-8.22 (4H, m);m/z MH⁺ 499.

Example 20:(R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph₃P)₄ (43.1 mg, 0.04 mmol) was added to(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 16) (300 mg, 0.75 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(sourced commercially) (236 mg, 0.75 mmol) and Na₂CO₃ (158 mg, 1.49mmol) in 1,4-dioxane (10 mL) and water (5 mL) at rt. The reactionmixture was stirred at 80° C. for 16 h, allowed to cool to rt andconcentrated in vacuo. The crude product was purified by flash C18chromatography, eluting with 5-100% MeCN in water (+0.1 mmol/L NH₄HCO₃),to afford the title compound (285 mg, 75%) as a white solid; ¹H NMR (400MHz, MeOD) 1.94-2.05 (1H, m), 2.31 (4H, s), 2.57 (11H, s), 2.75 (4H, s),2.86 (3H, s), 3.06 (2H, p), 3.22 (1H, dd), 3.38-3.49 (1H, m), 3.51-3.69(4H, m), 7.42 (2H, d), 8.14-8.22 (4H, m); m/z MH⁺ 512.

Example 21:(R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph₃P)₄ (51.7 mg, 0.04 mmol) was added to2-bromo-5-((4-methylpiperazin-1-yl)methyl)pyrazine (Intermediate 28)(121 mg, 0.45 mmol),(R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 27) (200 mg, 0.45 mmol) and Na₂CO₃ (95 mg, 0.89 mmol) intoluene (0.2 mL) and water (1 mL). The reaction mixture was stirred at80° C. for 16 h, allowed to cool to rt and concentrated in vacuo. Theresulting crude product was purified by flash C18 chromatography,eluting with 0-100% MeCN in water, to afford the title compound (11 mg,5%) as a yellow solid; ¹H NMR (300 MHz, CDCl₃) 1.91 (1H, dq), 2.21 (1H,dq), 2.40 (3H, s), 2.67 (14H, d), 2.80 (3H, s), 2.95 (3H, s), 3.16 (1H,dd), 3.35-3.67 (3H, m), 3.73 (2H, s), 6.59-6.68 (2H, m), 7.87-7.99 (2H,m), 8.56 (1H, d), 8.90 (1H, d); m/z MH⁺ 512.

Example 22:(R)-2,5,7-trimethyl-6-((1-(4-(2-((4-methylpiperazin-1-yl)methyl)pyrimidin-5-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph₃P)₄ (63.9 mg, 0.06 mmol) was added to(R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 27) (247 mg, 0.55 mmol),5-bromo-2-((4-methylpiperazin-1-yl)methyl)pyrimidine (Intermediate 29)(150 mg, 0.55 mmol) and Na₂CO₃ (117 mg, 1.11 mmol) in 1,4-dioxane (2 mL)and water (1 mL). The reaction mixture was stirred at 80° C. for 16 h,allowed to cool to rt and concentrated in vacuo. The resulting crudeproduct was purified by preparative HPLC to afford the title compound(40 mg, 14%) as a yellow solid; ¹H NMR (300 MHz, DMSO) 1.85 (1H, dq),2.10 (1H, dq), 2.26 (3H, s), 2.49 (4H, m), 2.63 (8H, m), 2.74 (3H, s),2.92 (2H, d), 3.06 (1H, dd), 3.26 (6H, m), 3.70 (2H, s), 6.64 (2H, d),7.62 (2H, d), 8.99 (2H, s); m/z MH⁺ 512.

Example 23:(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridin-3-yl)methyl)morpholine

RuPhos 3rd generation precatalyst (39 mg, 0.05 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (Intermediate 4) (150 mg, 0.47 mmol),4-((6-(4-bromophenyl)pyridin-3-yl)methyl)morpholine (Intermediate 31)(157 mg, 0.47 mmol), Cs₂CO₃ (768 mg, 2.36 mmol) and RuPhos (44 mg, 0.09mmol) in 1,4-dioxane (3 mL) at rt. The reaction mixture was stirred at90° C. for 16 h, allowed to cool to rt and concentrated in vacuo. Theresulting crude product was purified by preparative HPLC to afford thetitle compound (54 mg, 23%) as a white solid; ¹H NMR (300 MHz, MeOD)1.87-2.05 (1H, m), 2.22 (1H, dq), 2.50 (4H, dd), 2.55 (3H, s), 2.71 (4H,s), 2.82 (3H, s), 2.94-3.09 (2H, m), 3.16 (1H, dd), 3.32-3.51 (2H, m),3.54-3.63 (3H, m), 3.63-3.76 (4H, m), 6.61-6.73 (2H, m), 7.67-7.87 (4H,m), 8.44 (1H, d); m/z MH⁺ 498.

Example 24:(R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph₃P)₄ (26 mg, 0.02 mmol) was added to(R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 27) (100 mg, 0.22 mmol),3-chloro-6-((4-methylpiperazin-1-yl)methyl)pyridazine (Intermediate 32)(51 mg, 0.22 mmol) and Na₂CO₃ (47 mg, 0.45 mmol) in 1,4-dioxane (5 mL)and water (1 mL). The reaction mixture was stirred at 80° C. for 16 h,allowed to cool to rt and concentrated in vacuo. The resulting crudeproduct was purified by preparative HPLC to afford the title compound(35 mg, 31%) as a white solid; ¹H NMR (300 MHz, DMSO) 1.87 (1H, m), 2.15(4H, m), 2.20-2.50 (11H, m), 2.64 (4H, m), 2.75 (3H, s), 2.93 (2H, d),3.09 (1H, dd), 3.30-3.60 (3H, m), 3.74 (2H, s), 6.65 (2H, m), 7.59 (1H,d), 8.00 (3H, m); m/z MH⁺ 512.

Example 25:(R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

RuPhos 3rd generation precatalyst (36 mg, 0.04 mmol) and RuPhos (20 mg,0.04 mmol) was added to2-(4-bromophenyl)-5-((4-methylpiperazin-1-yl)methyl)pyrimidine(Intermediate 35) (150 mg, 0.43 mmol),(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (Intermediate 4) (137 mg, 0.43 mmol) and Cs₂CO₃ (563 mg,1.73 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at80° C. for 16 h, allowed to cool to rt and concentrated in vacuo. Theresulting crude product was purified by flash C18 chromatography,eluting with 0-100% MeCN in water, to afford the title compound (58 mg,26%) as a white solid; ¹H NMR (300 MHz, CDCl₃) 1.81-1.99 (2H, m), 2.19(1H, dt), 2.35 (3H, s), 2.67 (14H, m), 2.76-3.04 (5H, m), 3.18 (1H, dd),3.36-3.68 (5H, m), 6.55-6.66 (2H, m), 8.26-8.38 (2H, m), 8.64 (2H, s);m/z MH⁺ 512.

Example 26:(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyrazin-2-yl)methyl)morpholine

Pd(Ph₃P)₄ (34 mg, 0.03 mmol) was added to(R)-2,5,7-trimethyl-6-((1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 27) (130 mg, 0.29 mmol),4-((5-chloropyrazin-2-yl)methyl)morpholine (Intermediate 76) (62 mg,0.29 mmol) and Na₂CO₃ (62 mg, 0.58 mmol) in 1,4-dioxane (3 mL) and water(1.5 mL). The reaction mixture was stirred at 90° C. for 16 h, allowedto cool to rt and concentrated in vacuo. The resulting crude product waspurified by flash C18 chromatography, eluting with 0-100% MeCN in water(+0.1% FA), to afford the title compound (70 mg, 48%) as a pale yellowsolid; ¹H NMR (300 MHz, CDCl₃) 1.91 (1H, dq), 2.21 (1H, dq), 2.67 (11H,m), 2.80 (3H, s), 2.95 (2H, m), 3.16 (1H, dd), 3.35-3.54 (2H, m), 3.60(1H, td), 3.71 (2H, s), 3.77 (4H, t), 6.58-6.69 (2H, m), 7.88-8.00 (2H,m), 8.60 (1H, s), 8.91 (1H, d); m/z MH⁺ 499.

Example 27:(R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Formaldehyde (37% in water) (5 mL, 67.2 mmol) was added in one portionto (R)-tert-butyl4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridin-3-yl)methyl)piperazine-1-carboxylate(Intermediate 82) (290 mg, 0.49 mmol) in formic acid (10 mL) at rt. Thereaction mixture was stirred at 55° C. for 4 h, allowed to cool to rtand concentrated in vacuo. The residue was redissolved in 2 M NH₃/MeOHand was purified by preparative HPLC to afford the title compound (58mg, 26%) as a white solid; ¹H NMR (500 MHz, CDCl₃) 1.83-1.93 (1H, m),2.12-2.22 (1H, m), 2.29 (3H, s), 2.53 (8H, d), 2.62 (4H, s), 2.70 (3H,s), 2.79 (3H, s), 2.85-2.99 (2H, m), 3.14 (1H, dd), 3.37-3.47 (2H, m),3.52 (2H, s), 3.57 (1H, td), 6.55-6.65 (2H, m), 7.59 (1H, dd), 7.65 (1H,dd), 7.87-7.95 (2H, m), 8.51 (1H, d); m/z MH⁺ 511.

Example 28:(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine

RuPhos 3rd generation precatalyst (53 mg, 0.06 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (Intermediate 4) (200 mg, 0.63 mmol),4-((5-(4-bromophenyl)pyrimidin-2-yl)methyl)morpholine (Intermediate 39)(231 mg, 0.69 mmol), Cs₂CO₃ (819 mg, 2.51 mmol) and Ruphos (59 mg, 0.13mmol) in 1,4-dioxane (8 mL). The reaction mixture was stirred at 90° C.for 16 h, allowed to cool to it and concentrated in vacuo. The resultingcrude product was purified by flash C18 chromatography, eluting with0-100% MeCN in water (+0.1% FA), to afford the tide compound (180 mg,57%) as a white solid; ¹H NMR (300 MHz, MeOD) 1.88-2.06 (1H, m), 2.22(1H, dq), 2.55 (3H, s), 2.60-2.69 (4H, m), 2.71 (4H, m), 2.82 (3H, s),3.02 (2H, dd), 3.15 (1H, dd), 3.31-3.50 (2H, m), 3.52-3.66 (1H, m),3.69-3.79 (4H, m), 3.83 (2H, s), 6.67-6.77 (2H, m), 7.52-7.63 (2H, m),8.97 (2H, s); m/z MH⁺ 499.

Example 29:(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine

Degassed 1,4-dioxane (10 mL) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 4) (257 mg, 1.05 mmol) and4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine (Intermediate 65)(350 mg, 1.05 mmol). Cs₂CO₃ (1.02 g, 3.14 mmol) was then added followedby RuPhos (24 mg, 0.05 mmol) and RuPhos 3rd generation precatalyst (44mg, 0.05 mmol). The reaction mixture was heated at 90° C. for 6 h,allowed to cool to rt, diluted with DCM (50 mL) and filtered. Thefiltrate was concentrated in vacuo. The resulting crude product waspurified by fcc, eluting with 0-5% 1 M NH/MeOH in DCM. The resulting oilwas triturated with EtOAc:heptane (4:1, 10 mL) and the precipitate wasisolated by filtration and dried in vacuo to afford the title compound(270 mg, 52%) as a yellow solid: ¹H NMR (500 MHz, CDCl₃) 1.90 (1H, dq),2.20 (1H, td), 2.56 (4H, q), 2.62 (4H, s), 2.70 (3H, s), 2.79 (3H, s),2.93 (2H, qd), 3.15 (1H, dd), 3.37-3.49 (2H, m), 3.55-3.63 (1H, m),3.69-3.77 (4H, m), 3.87 (2H, s), 6.59-6.68 (2H, m), 7.59 (1H, d), 7.75(1H, d), 7.98-8.06 (2H, m); m/z MH⁺ 499.

Example 30:(S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine

Example 30 was prepared in a similar way to Example 29 in 5 steps fromcommercially available (S)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate to afford the title compound(122 mg, 30% final step) as a white solid; ¹H NMR (500 MHz, DMSO) 1.86(1H, dq), 2.07-2.16 (1H, m), 2.38-2.45 (4H, m), 2.47 (3H, s), 2.59 (1H,d), 2.64 (3H, s), 2.74 (3H, s), 2.93 (2H, d), 3.09 (1H, dd), 3.32 (1H,d), 3.43 (1H, dd), 3.46-3.53 (1H, m), 3.54-3.63 (4H, m), 3.75 (2H, s),6.65 (2H, d), 7.62 (1H, d), 7.98 (2H, d), 8.02 (1H, d); m/z MH⁺ 499.

Example 31:(R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

XPhos 2^(nd) generation precatalyst (30 mg, 0.04 mmol) was added to(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid(Intermediate 42) (112 mg, 0.42 mmol),(R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 45) (160 mg, 0.38 mmol) and Cs₂CO₃ (250 mg, 0.77 mmol) in1,4-dioxane (2 mL) and water (1 mL) at rt. The reaction mixture wasstirred at 80° C. for 16 h, allowed to cool to rt and concentrated invacuo. The resulting crude product was purified by preparative HPLC toafford the title compound (90 mg, 42%) as a white solid; ¹H NMR (300MHz, CDCl₃) 1.78-2.24 (3H, m), 2.27 (3H, s), 2.31-2.77 (17H, m), 2.82(3H, s), 2.87-3.06 (2H, m), 3.34 (1H, dd), 3.45-3.61 (3H, m), 3.66-3.83(5H, m), 6.93-7.04 (2H, m), 7.22 (1H, d), 7.77 (1H, s); m/z MH⁺ 556.

Example 32:2,5,7-trimethyl-6-(((R)-1-(5-(4-(((3R,5S)-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

(2S,6R)-1,2,6-trimethylpiperazine (sourced commercially) (104 mg, 0.81mmol) was added in one portion to(R)-6-((1-(5-(4-(chloromethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 48) (181 mg, 0.40 mmol) and triethylamine (0.28 mL, 2.02mmol) in THF (5 mL) at rt under air. The reaction mixture was stirred at60° C. for 24 h, allowed to cool to rt, and diluted with EtOAc (50 mL)and water (15 mL). The organic layer was isolated and washed with sat.brine (15 mL), dried over MgSO₄, filtered and concentrated in vacuo. Theresulting crude product was purified by fcc, eluting with 0-4% 1 MNH₃/MeOH in DCM, to afford the title compound (115 mg, 53%) as a paleyellow solid; ¹H NMR (500 MHz, DMSO) 0.92 (6H, d), 1.75 (2H, t),1.8-1.91 (1H, m), 2.06-2.16 (5H, m), 2.46 (3H, s), 2.5-2.52 (1H, m),2.63 (6H, d), 2.74 (3H, s), 2.93 (2H, d), 3.2-3.26 (1H, m), 3.37-3.47(3H, m), 3.63 (1H, dd), 3.66-3.73 (1H, m), 7.32 (2H, d), 7.87 (2H, d),8.02 (1H, d), 8.61 (1H, d); m/z MH⁺ 540.

Example 33:6-(((R)-1-(5-(4-(((R)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (200 mg, 0.47 mmol) and (R)-1,2-dimethylpiperazine(sourced commercially) (267 mg, 2.34 mmol) in MeOH (10 mL) was stirredat rt for 1 h, then sodium triacetoxyborohydride (397 mg, 1.87 mmol) andAcOH (2.81 mg, 0.05 mmol) were added and the reaction mixture wasstirred at rt for 16 h, then concentrated in vacuo. The resulting crudeproduct was purified by preparative HPLC to afford the title compound(126 mg, 51%) as a white solid; ¹H NMR (300 MHz, CDCl₃) 1.06 (3H, d),1.93 (2H, dq), 2.22 (3H, dt), 2.33 (4H, s), 2.56-3.06 (15H, m), 3.34(1H, dd), 3.56 (3H, d), 3.67-3.84 (2H, m), 7.40 (2H, d), 7.78-7.88 (2H,m), 7.95 (1H, d), 8.51 (1H, d); m/z MH⁺ 526.

Example 34:6-(((R)-1-(5-(4-(((R)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-1,3-dimethylpiperazine dihydrochloride (sourced commercially) (167mg, 0.89 mmol) was added in one portion to(R)-6-((1-(5-(4-(chloromethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 48) (200 mg, 0.45 mmol) and triethylamine (0.31 mL, 2.23mmol) in 1,4-dioxane (5 mL) at rt under air. The reaction mixture wasstirred at 80° C. for 24 h, allowed to cool to rt and diluted with EtOAc(50 mL) and water (15 mL). The organic layer was isolated and washedwith sat. brine (15 mL), dried over MgSO₄, filtered and concentrated invacuo. The resulting crude product was purified by fcc, eluting with0-4% 1 M NH₃/MeOH in DCM, then further purified by preparative HPLC toafford the title compound (32 mg, 14%) as a yellow foam; ¹H NMR (500MHz, DMSO) 1.06 (3H, d), 1.79-1.91 (2H, m), 1.99 (1H, s), 2.10 (5H, s),2.41 (1H, s), 2.46 (4H, s), 2.52-2.62 (3H, m), 2.63 (3H, s), 2.74 (3H,s), 2.93 (2H, d), 3.12 (1H, d), 3.23 (1H, dd), 3.4-3.49 (1H, m), 3.63(1H, dd), 3.65-3.74 (1H, m), 3.95 (1H, d), 7.32 (2H, d), 7.82-7.90 (2H,m), 8.02 (1H, d), 8.60 (1H, d); m/z MH⁺ 526.

Example 35:2,5,7-trimethyl-6-(((R)-1-(5-(4-(((2R,5R)-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

(2R,5R)-1,2,5-trimethylpiperazine hydrochloride (sourced commercially)(147 mg, 0.89 mmol) was added in one portion to(R)-6-((1-(5-(4-(chloromethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 48) (200 mg, 0.45 mmol) and triethylamine (0.31 mL, 2.23mmol) in 1,4-dioxane (5 mL) at rt under air. The reaction mixture wasstirred at 80° C. for 24 h, allowed to cool to rt and diluted with EtOAc(50 mL) and water (15 mL). The organic layer was isolated and washedwith sat. brine solution (15 ml), dried over MgSO₄, filtered and driedin vacuo. The resulting crude product was purified by fcc, eluting with0-4% 1 M NH₃/MeOH in DCM, then further purified by trituration with MeOHto afford the title compound (78 mg, 32%) as a pale yellow solid; ¹H NMR(500 MHz, DMSO) 0.90 (3H, d), 1.03 (3H, d), 1.8-1.91 (1H, m), 2.10 (5H,s), 2.22-2.32 (3H, m), 2.46 (4H, s), 2.57-2.61 (1H, m), 2.63 (3H, s),2.74 (4H, s), 2.93 (2H, d), 3.23 (1H, dd), 3.41-3.48 (2H, m), 3.55-3.66(2H, m), 3.66-3.73 (1H, m), 7.35 (2H, d), 7.86 (2H, d), 8.02 (1H, d),8.60 (1H, d); m/z MH⁺ 540.

Example 36:2,5,7-trimethyl-6-(((R)-1-(5-(4-(((2S,5R)-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

(2R,5S)-1,2,5-trimethylpiperazine dihydrochloride (sourced commercially)(180 mg, 0.89 mmol) was added in one portion to(R)-6-((1-(5-(4-(chloromethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 48) (200 mg, 0.45 mmol) and triethylamine (0.31 mL, 2.23mmol) in 1,4-dioxane (5 mL) at rt under air. The reaction mixture wasstirred at 80° C. for 24 h, allowed to cool to rt and diluted with EtOAc(50 mL) and water (15 mL). The organic layer was isolate and washed withsat. brine solution (15 mL), dried over MgSO₄, filtered and concentratedin vacuo. The resulting crude product was purified by fcc, eluting with0-4% 1 M NH₃/MeOH in DCM, then further purified by preparative HPLC toafford the title compound (81 mg, 34%) as a pale yellow solid; ¹H NMR(500 MHz, DMSO) 0.83 (3H, d), 1.07 (3H, d), 1.73 (1H, t), 1.80-1.93 (3H,m), 2.09 (4H, s), 2.35 (1H, s), 2.46 (3H, s), 2.63 (5H, s), 2.74 (3H,s), 2.93 (2H, d), 3.01 (1H, d), 3.20-3.26 (1H, m), 3.43 (1H, d),3.59-3.74 (2H, m), 4.02 (1H, d), 7.32 (2H, d), 7.86 (2H, d), 8.02 (1H,s), 8.61 (1H, s), 1H missing assumed to be under DMSO peak; m/z MH⁺ 540.

Example 37:2,5,7-trimethyl-6-[[(3R)-1-[5-[4-(1-piperidylmethyl)phenyl]pyrazin-2-yl]pyrrolidin-3-yl]methyl]-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (30 mg, 0.07 mmol), piperidine (12 mg, 0.14 mmol), DCM(2 mL) and AcOH (2 drop) were combined and the reaction mixture wasstirred at rt for 5 h. Sodium triacetoxyborohydride (45 mg, 0.21 mmol)was added and the reaction mixture was stirred at rt for 16 h. Theresulting crude product was purified by preparative HPLC to afford thetitle compound (15 mg, 44%); 1H NMR (400 MHz, DMSO) 1.47 (6H, d),1.82-1.92 (1H, m), 2.12 (1H, dd), 2.36 (4H, s), 2.48 (3H, s), 2.65 (4H,s), 2.76 (3H, s), 2.95 (2H, d), 3.25 (2H, dd), 3.41-3.51 (2H, m),3.62-3.75 (2H, m), 7.37 (2H, s), 7.90 (2H, s), 8.04 (1H, d), 8.64 (1H,s); m/z MH⁺ 497.

Example 38:(R)-6-((1-(5-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

1-Ethylpiperazine (136 mg, 1.19 mmol) was added to(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (170 mg, 0.40 mmol) in MeOH (5 mL) at rt, and thereaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (421mg, 1.99 mmol) was added. The reaction mixture was stirred at rt for 60h, then was concentrated in vacuo. The resulting crude product waspurified by flash C18 chromatography, eluting with 5-100% MeCN in water(+0.1% FA), to afford the formic acid salt of the title compound (114mg, 51%) as a pale yellow solid; ¹H NMR (300 MHz, CDCl₃) 1.25 (3H, t),1.93 (1H, dq), 2.15-2.32 (1H, m), 2.56-3.06 (22H, m), 3.34 (1H, dd),3.48-3.65 (3H, m), 3.76 (2H, ddt), 7.34-7.44 (2H, m), 7.78-7.89 (2H, m),7.95 (1H, d), 8.47-8.55 (2H, m); m/z MH⁺ 526.

Example 39:(R)-2,5,7-trimethyl-6-((1-(5-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Bis(triphenylphosphoranyl)palladium(IV) chloride (35 mg, 0.05 mmol) wasadded to 1-((6-bromopyridin-3-yl)methyl)-4-methylpiperazine(Intermediate 7) (135 mg, 0.50 mmol), 1,1,1,2,2,2-hexamethyldistannane(180 mg, 0.55 mmol) in THF (3 mL) at rt. The reaction mixture wasstirred at 85° C. for 16 h.(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 46) (200 mg, 0.50 mmol) and Pd(Ph₃P)₄ (57.4 mg, 0.05 mmol)and THF (5 mL) were added. The reaction mixture was transferred to amicrowave vial and was heated at 100° C. for 10 h in a microwave reactorand then allowed to cool to rt and concentrated in vacuo. The resultingcrude product was purified by flash C18 chromatography, eluting with5-100% MeCN in water (+0.1% FA), to afford the title compound (59 mg,23%) as a yellow solid; ¹H NMR (400 MHz, CDCl₃) 1.95 (1H, dq), 2.25 (1H,tt), 2.47 (3H, s), 2.60-2.75 (15H, m), 2.82 (3H, s), 2.97 (2H, qd), 3.38(1H, dd), 3.54-3.65 (3H, m), 3.80 (2H, td), 7.73 (1H, dd), 7.92 (1H, d),8.11 (1H, d), 8.53-8.59 (1H, m), 9.09 (1H, d); m/z MH⁺ 513.

Example 40:6-(((R)-1-(5-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (200 mg, 0.47 mmol) was added to(2R,6S)-1,2,6-trimethylpiperazine (sourced commercially) (120 mg, 0.94mmol) in DCM (10 mL). The reaction mixture was stirred at rt for 2 h.AcOH (2.7 μl, 0.05 mmol) and sodium cyanoborohydride (118 mg, 1.87 mmol)were added and the reaction mixture was stirred for 16 h, then wasconcentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (75 mg, 31%) as a whitesolid; ¹H NMR (300 MHz, CDCl₃) 1.06 (6H, d), 1.73 (2H, t), 1.93 (1H,dq), 2.23 (1H, dq), 2.82 (17H, m), 3.34 (1H, dd), 3.55 (3H, d), 3.75(2H, m), 7.40 (2H, m), 7.83 (2H, m), 7.95 (1H, d), 8.51 (1H, d): m/z MH⁺526.

Example 41:2-{4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazin-1-yl}ethanol

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (30 mg, 0.07 mmol), 2-piperazin-1-ylethanol (18.23 mg,0.14 mmol), DCM (2 mL) and AcOH (2 drop) were combined and the reactionmixture was stirred at it for 5 h. Sodium triacetoxyborohydride (45 mg,0.21 mmol) was then added and the reaction mixture was stirred at rt for16 h. The resulting crude product was purified by preparative HPLC toafford the title compound (8 mg, 20%); ¹H NMR (400 MHz, DMSO) 1.81-1.93(1H, m), 2.12 (1H, d), 2.31-2.44 (10H, m), 2.48 (3H, s), 2.65 (4H, s),2.76 (3H, s), 2.95 (2H, d), 3.22-3.27 (2H, m), 3.47 (4H, s), 3.62-3.76(2H, m) 4.32 (1H, s), 7.34 (2H, d), 7.88 (2H, d), 8.04 (1H, d), 8.62(1H, d); m/z MH⁺ 542.

Example 42:(R)-6-((1-(5-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

1-(2-Methoxyethyl)piperazine (202 mg, 1.40 mmol) was added to(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (200 mg, 0.47 mmol) in DCM (5 mL) at rt under air andthe reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride(496 mg, 2.34 mmol) was added and the reaction mixture was stirred at rtfor 16 h, then concentrated in vacuo. The resulting crude product waspurified by flash C18 chromatography, eluting with 5-100% MeCN in water(+), 1% FA), to afford the formic acid salt of the title compound (194mg, 70%) as a yellow solid; ¹H NMR (400 MHz, CDCl₃) 1.89-2.01 (1H, m),2.18-2.31 (1H, m), 2.59-3.05 (22H, m), 3.35 (4H, s), 3.52-3.67 (3H, m),3.67-3.83 (4H, m), 7.38-7.46 (2H, m), 7.82-7.90 (2H, m), 7.97 (1H, s),8.45 (1H, s), 8.54 (1H, d); m/z MH⁺ 556.

Example 43:(R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

XPhos 2^(nd) generation precatalyst (14.7 mg, 0.02 mmol) was added to(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 46) (150 mg, 0.37 mmol),(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid(Intermediate 42) (108 mg, 0.41 mmol) and Cs₂CO₃ (243 mg, 0.75 mmol) in1,4-dioxane (3 mL) and water (1.5 mL) at rt. The reaction mixture wasstirred at 90° C. for 4 h, allowed to cool to rt and concentrated invacuo. The resulting crude product was purified by flash C18chromatography, eluting with 5-100% MeCN in water (+0.1% FA), to affordthe formic acid salt of the title compound (168 mg, 79%) as a paleyellow solid; ¹H NMR (400 MHz, CDCl₃) 1.93 (1H, dq), 2.23 (1H, dq),2.54-3.05 (24H, m), 3.34 (1H, dd), 3.51-3.65 (3H, m), 3.76 (2H, ddd),3.89 (3H, s), 6.96-7.06 (2H, m), 7.73 (1H, d), 7.98 (1H, d), 8.69 (1H,d); m/z MH⁺ 542.

Example 44:{1-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperidin-4-yl}methanol

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (30 mg, 0.07 mmol), 4-piperidylmethanol (16.12 mg,0.14 mmol), DCM (2 mL) and AcOH (2 drop) were combined, and the reactionmixture was stirred at rt for 5 h. Sodium triacetoxyborohydride (45 mg,0.21 mmol) was then added and the reaction mixture was stirred at rt for16 h. The mixture was purified by preparative HPLC to afford the titlecompound (17.4 mg, 47%); ¹H NMR (400 MHz, DMSO) 1.07-1.2 (2H, m), 1.34(1H, s), 1.62 (2H, d), 1.85-1.95 (3H, m), 2.12 (1H, dd), 2.48 (3H, s),2.65 (4H, s), 2.76 (3H, s), 2.82 (2H, d), 2.95 (2H, d), 3.21-3.28 (4H,m), 3.45 (2H, s), 3.62-3.75 (2H, m), 4.37 (1H, s), 7.34 (2H, d), 7.88(2H, d), 8.04 (1H, d), 8.62 (1H, d); m/z MH⁺ 527.

Example 45:6-{[(3R)-1-(5-{4-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}pyrazin-2-yl)pyrrolidin-3-yl]methyl}-2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (30 mg, 0.07 mmol), 1,4-thiazinane 1,1-dioxidehydrochloride salt (24.03 mg, 0.14 mmol), DCM (2 mL) and AcOH (2 drop)were combined and the mixture was stirred at rt for 5 h. Sodiumtriacetoxyborohydride (45 mg, 0.21 mmol) was then added and the reactionmixture was stirred at rt for 16 h. The mixture was purified bypreparative HPLC to afford the title compound (12 mg, 30%); ¹H NMR (400MHz, DMSO) 1.87 (1H, dd), 2.12 (1H, dd), 2.48 (3H, s), 2.65 (4H, s),2.76 (3H, s), 2.86-2.93 (4H, m), 2.95 (2H, d), 3.09-3.14 (4H, m), 3.25(1H, dd), 3.45 (1H, dt), 3.62-3.76 (4H, m), 7.39 (2H, d), 7.91 (2H, d),8.04 (1H, d), 8.64 (1H, d); m/z MH⁺ 547.

Example 46:2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperidin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin-3-yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (30 mg, 0.07 mmol), 4-methylsulfonylpiperidine (22.9mg, 0.14 mmol), DCM (2 mL) and AcOH (2 drop) were combined and themixture was stirred at rt for 5 h. Sodium triacetoxyborohydride (45 mg,0.21 mmol) was then added and the reaction mixture was stirred at rt for16 h. The mixture was purified by preparative HPLC and lyophilized toafford the title compound (15 mg, 38%); ¹H NMR (500 MHz, DMSO) 1.56 (2H,tt), 1.76-1.85 (1H, m), 1.92 (4H, t), 2.05 (1H, dd), 2.41 (3H, s), 2.58(4H, s), 2.69 (3H, s), 2.84 (3H, s), 2.88 (4H, d), 2.98 (1H, ddt), 3.18(1H, dd), 3.38 (1H, dt), 3.44 (2H, s), 3.55-3.68 (2H, m), 7.28 (2H, d),7.82 (2H, d), 7.97 (1H, d), 8.55 (1H, d); m/z MH⁺ 575.

Example 47:(R)-4-((6-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-3-yl)methyl)morpholine

Bis(triphenylphosphoranyl)palladium(IV) chloride (164 mg, 0.23 mmol) wasadded to 4-((6-bromopyridin-3-yl)methyl)morpholine (Intermediate 30)(600 mg, 2.33 mmol), 1,1,1,2,2,2-hexamethyldistannane (841 mg, 2.57mmol) in THF (8 mL) at rt. The reaction mixture was stirred at 85° C.for 16 h.(R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 45) (300 mg, 0.72 mmol) and Pd(Ph₃P)₄ (83 mg, 0.07 mmol)were added and the mixture was transferred to a microwave tube with THF(10 mL). The reaction mixture was heated at 100° C. for 5 h in themicrowave reactor and allowed to cool to rt, then concentrated in vacuo.The resulting crude product was purified by flash C18 chromatography,eluting with 5-100% MeCN in water (+0.1% FA), then further purified bypreparative HPLC to afford the title compound (160 mg, 43%) as a whitesolid; ¹H NMR (300 MHz, MeOD) 1.97 (1H, dq), 2.24 (1H, dq), 2.47-2.59(10H, m), 2.73 (4H, s), 2.84 (3H, s), 3.04 (2H, dd), 3.32-3.42 (1H, m),3.47-3.66 (3H, m), 3.66-3.87 (6H, m), 7.72 (1H, dd), 7.81 (1H, s), 7.91(1H, dd), 8.53-8.60 (1H, m); m/z MH⁺ 514.

Example 48:6-(((R)-1-(5-(4-(((S)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (200 mg, 0.47 mmol) was added to(S)-1,2-dimethylpiperazine dihydrochloride (350 mg, 1.87 mmol) in MeOH(10 mL). The reaction mixture was stirred at rt for 2 h. AcOH (2.81 mg,0.05 mmol) and sodium triacetoxyborohydride (397 mg, 1.87 mmol) wereadded and the reaction mixture was stirred for 16 h. The reactionmixture was quenched with water and the resulting solution was purifiedby preparative HPLC to afford the title compound (132 mg, 54%) as awhite solid; ¹H NMR (400 MHz, CDCl₃) 1.07 (3H, d), 1.94 (2H, dq),2.18-2.35 (6H, m), 2.39 (1H, s), 2.59-2.85 (13H, m), 2.97 (2H, qd), 3.35(1H, dd), 3.56 (3H, d), 3.76 (2H, ddt), 7.38-7.45 (2H, m), 7.80-7.88(2H, m), 7.96 (1H, d), 8.52 (1H, d); m/z MH⁺ 526.

Example 49:(R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-2-yl)methyl)morpholine

XPhos 2^(nd) generation precatalyst (19.6 mg, 0.02 mmol) was added to(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 46) (200 mg, 0.50 mmol),(6-(morpholinomethyl)pyridin-3-yl)boronic acid (sourced commercially)(110 mg, 0.50 mmol) and Cs₂CO₃ (324 mg, 0.99 mmol) in 1,4-dioxane (4 mL)and water (2 mL) at it. The reaction mixture was stirred at 80° C. for16 h, allowed to cool to rt and concentrated in vacuo. The resultingcrude product was purified by preparative HPLC to afford the titlecompound (172 mg, 69%) as a yellow solid; ¹H NMR (400 MHz, MeOD)1.91-2.06 (1H, m), 2.23-2.29 (1H, m), 2.53-2.57 (7H, m), 2.66-2.74 (4H,m), 2.85 (3H, d), 2.97-3.11 (2H, m), 3.35-3.38 (1H, m), 3.53-3.59 (1H,m), 3.67-3.85 (8H, m), 7.61 (1H, d), 8.05 (1H, s), 8.30 (1H, dd), 8.56(1H, s), 9.01-9.02 (1H, m) m/z MH⁺ 500.

Example 50:6-(((R)-1-(5-(4-(((S)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

(S)-1,3-Dimethylpiperazine dihydrochloride (167 mg, 0.89 mmol) was addedin one portion to(R)-6-((1-(5-(4-(chloromethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 48) (200 mg, 0.45 mmol) and triethylamine (0.31 mL, 2.23mmol) in 1,4-dioxane (5 mL) at rt under air. The reaction mixture wasstirred at 80° C. for 24 h, allowed to cool to rt and diluted with EtOAc(50 mL) and water (15 mL). The organic layer was isolated and washedwith sat. brine (15 mL), dried over MgSO₄, filtered and concentrated invacuo. The resulting crude product was purified by fcc, eluting with0-4% 1 M NH₃/MeOH in DCM to afford the title compound (54 mg, 23%) as apale yellow solid; ¹H NMR (500 MHz, DMSO) 1.06 (3H, d), 1.80-1.91 (2H,m), 1.94-2.04 (1H, m), 2.05-2.14 (5H, m), 2.37-2.43 (1H, m), 2.46 (4H,s), 2.52-2.61 (3H, m), 2.63 (3H, s), 2.74 (3H, s), 2.93 (2H, d), 3.12(1H, d), 3.23 (1H, dd), 3.43 (1H, dt), 3.63 (1H, dd), 3.66-3.73 (1H, m),3.95 (1H, d), 7.33 (2H, d), 7.82-7.91 (2H, m), 8.02 (1H, d), 8.60 (1H,d); m/z MH⁺ 526.

Example 51:(R)-4-(4-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine

XPhos 2^(nd) generation precatalyst (11.3 mg, 0.01 mmol) was added to4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine(sourced commercially) (87 mg, 0.29 mmol),(R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 45) (120 mg, 0.29 mmol) and Cs₂CO₃ (188 mg, 0.58 mmol) in1,4-dioxane (4 mL) and water (1.5 mL). The reaction mixture was stirredat 90° C. for 16 h, allowed to cool to rt and filtered through celite.The filtrate was concentrated in vacuo and the resulting crude productwas purified by preparative HPLC to afford the title compound (49 mg,31%) as a pale yellow solid; ¹H NMR (300 MHz, MeOD) 1.92-1.99 (1H, m),2.17-2.27 (1H, m), 2.41 (3H, s), 2.55 (3H, s), 2.61-2.83 (11H, m),2.96-3.03 (2H, m), 3.29-3.35 (1H, m), 3.47-3.55 (10H, m), 3.65-3.79 (6H,m), 3.86 (2H, s), 7.47-7.53 (4H, m), 7.75 (1H, s); m/z MH⁺ 513.

Example 52:2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin-3-yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (30 mg, 0.07 mmol), 1-methylsulfonylpiperazine (22.99mg, 0.14 mmol), DCM (2 mL) and AcOH (2 drop) were combined and themixture was stirred at rt for 5 h. Sodium triacetoxyborohydride (45 mg,0.21 mmol) was then added and the reaction mixture was stirred at rt for16 h. The mixture was purified by preparative HPLC to afford the titlecompound (11.9 mg, 30%); ¹H NMR (400 MHz, DMSO) 1.87 (1H, dd), 2.12 (1H,dd), 2.48 (7H, s), 2.65 (4H, s), 2.76 (3H, s), 2.87 (3H, s), 2.95 (2H,d), 3.09-3.16 (4H, m), 3.25 (1H, dd), 3.41-3.50 (1H, m), 3.55 (2H, s),3.62-3.75 (2H, m), 7.37 (2H, d), 7.90 (2H, d), 8.04 (1H, d), 8.63 (1H,d); m/z MH⁺ 576.

Example 53:(R)—N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)acetamide

N,N-dimethyl-2-(piperazin-1-yl)acetamide (Intermediate 21) (240 mg, 1.40mmol) was added to(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (200 mg, 0.47 mmol) in DCM (5 mL) at rt, and thereaction mixture was stirred for 1 h. Sodium triacetoxyborohydride (496mg, 2.34 mmol) was added and the reaction mixture was stirred at rt for16 h, then concentrated in vacuo. The resulting crude product waspurified by flash C18 chromatography, eluting with 5-100% MeCN in water(+0.1% FA) to afford a partial (0.6 equivalents) formic acid salt of thetitle compound (172 mg, 60%) as a yellow solid; ¹H NMR (400 MHz, CDCl₃)1.87-2.01 (1H, m), 2.18-2.30 (1H, m), 2.64 (31H, s), 2.60-2.71 (1H, m),2.72-2.78 (11H, m), 2.83 (3H, s), 2.96 (3H, s), 2.88-3.05 (2H, m), 3.05(3H, s), 3.24 (2H, s), 3.35 (1H, dd), 3.52-3.63 (1H, m), 3.72-3.81 (1H,m), 3.78 (3H, s), 7.45 (2H, d), 7.87 (2H, d), 7.97 (1H, d), 8.42 (0.6Hs, equates to 0.6 eq. formate salt), 8.52 (1H, d); m/z MH⁺ 583.

Example 54:(R)-2,5,7-trimethyl-6-((1-(6-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

XPhos 2^(nd) generation precatalyst (28 mg, 0.04 mmol) was added to1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(125 mg, 0.40 mmol),(R)-6-((1-(5-bromo-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 45) (150 mg, 0.36 mmol) and Cs₂CO₃ (235 mg, 0.72 mmol) in1,4-dioxane (3 mL) and water (1.5 mL) at rt. The reaction mixture wasstirred at 90° C. for 16 h, allowed to cool to rt and concentrated invacuo. The resulting crude product was purified by preparative HPLC toafford the title compound (110 mg, 58%) as a white solid; ¹H NMR (300MHz, CDCl₃) 1.81-2.00 (1H, m), 2.20 (1H, dq), 2.31-2.76 (21H, m), 2.82(3H, s), 2.94 (2H, qd), 3.34 (1H, dd), 3.46-3.61 (3H, m), 3.74 (2H,ddd), 7.38 (2H, d), 7.43-7.53 (2H, m), 7.79 (1H, s); m/z MH⁺ 526.

Example 55:N,N-dimethyl-4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazine-1-carboxamide

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (30 mg, 0.07 mmol),N,N-dimethylpiperazine-1-carboxamide (23 mg, 0.14 mmol), DCM (2 mL) andAcOH (2 drop) were combined and the mixture was stirred at rt for 5 h.Sodium triacetoxyborohydride (45 mg, 0.21 mmol) was then added and thereaction mixture was stirred at rt for 16 h. The mixture was purified bypreparative HPLC to afford the title compound (13 mg, 33%); ¹H NMR (400MHz, DMSO) 1.82-1.92 (1H, m), 2.07-2.17 (1H, m), 2.35-2.41 (4H, m) 2.48(3H, s), 2.65 (4H, s), 2.72 (6H, s), 2.76 (3H, s), 2.95 (2H, d),3.07-3.15 (4H, m), 3.22-3.27 (1H, m), 3.41-3.54 (3H, m), 3.68 (2H, ddd),7.36 (2H, d), 7.89 (2H, d), 8.04 (1H, d), 8.63 (1H, d); m/z MH⁺ 569.

Example 56:(R)-2,5,7-trimethyl-6-((1-(5-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Pd(Ph₃P)₄ (35 mg, 0.03 mmol) was added to(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 46) (122 mg, 0.30 mmol),1-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(Intermediate 51) (100 mg, 0.30 mmol) and Na₂CO₃ (64.2 mg, 0.61 mmol) intoluene (4 mL) and water (1 mL). The reaction mixture was stirred at 80°C. for 16 h, allowed to cool to rt and concentrated in vacuo. Theresulting crude product was purified by preparative HPLC to afford thetitle compound (15 mg, 9%) as a white solid; ¹H NMR (300 MHz, CDCl₃)1.94 (1H, m), 2.22 (1H, dt), 2.30-2.75 (21H, m), 2.81 (3H, s), 2.95 (2H,t), 3.34 (1H, dd), 3.54 (3H, m), 3.75 (2H, m), 7.34 (1H, m), 7.65 (2H,m), 7.94 (1H, d), 8.50 (1H, s); m/z MH⁺ 526.

Example 57:(R)-2,5,7-trimethyl-6-((1-(5-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

XPhos 2^(nd) generation precatalyst (10.76 mg, 0.01 mmol) was added to(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 46) (110 mg, 0.27 mmol),(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)boronic acid(Intermediate 9) (71 mg, 0.30 mmol) and Cs₂CO₃ (178 mg, 0.55 mmol) in1,4-dioxane (3 mL) and water (1.5 mL) at rt. The reaction mixture wasstirred at 80° C. for 4 h, allowed to cool to rt and concentrated invacuo. The resulting crude product was purified by flash C18chromatography, eluting with 5-100% MeCN in water (+0.1% FA) to affordthe partial (0.5 eq.) formic acid salt of the title compound (141 mg,96%) as a white solid; ¹H NMR (400 MHz, CDCl₃) 1.96 (1H, dq), 2.25 (1H,dt), 2.62-2.76 (1H, m), 2.83 (3H, s), 2.89-3.06 (10H, m), 3.36 (1H, dd),3.59 (1H, dt), 3.71-3.84 (4H, m), 7.41 (1H, d), 7.99 (1H, d) 8.18 (1H,dd), 8.40 (0.5H, s, from 0.5 eq formate salt), 8.53 (1H, d), 9.11 (1H,d); m/z MH⁺ 513.

Example 58:(R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)ethanone

1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)ethanone(Intermediate 52) (667 mg, 1.94 mmol),(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 46) (600 mg, 1.49 mmol) and Cs₂CO₃ (972 mg, 2.98 mmol)were added to 1,4-dioxane (30 mL) and water (15 mL) and the mixture wasdegassed for 10 min. XPhos 2^(nd) generation precatalyst (59 mg, 0.07mmol) was added and the reaction mixture was stirred for 18 h at 90° C.,then allowed to cool to rt and diluted with EtOAc (50 mL). The organiclayer was isolated and washed with sat. brine solution and dried overMgSO₄, filtered and concentrated in vacuo. The resulting crude productwas purified by fcc, eluting with 0-4% 1 M NH₃/MeOH in DCM. The productwas dissolved in EtOAc (2 mL) and stirred for 2 h, and the resultingprecipitate was isolated by filtration and dried in vacuo to afford thetitle compound (209 mg, 26%) as a white solid; ¹H NMR (500 MHz, DMSO)1.78-1.91 (1H, m), 1.96 (3H, s), 2.03-2.16 (1H, m), 2.26-2.33 (2H, m),2.34-2.4 (2H, m), 2.46 (3H, s), 2.55-2.67 (4H, m), 2.74 (3H, s), 2.93(2H, d), 3.2-3.26 (1H, m), 3.35-3.47 (5H, m), 3.50 (2H, s), 3.59-3.75(2H, m), 7.34 (2H, d), 7.88 (2H, d), 8.02 (1H, s), 8.62 (1H, s); m/z MH⁺540.

Example 59:(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

XPhos 2^(nd) generation precatalyst (0.780 g, 0.99 mmol) was added to amixture of(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 46) (7.98 g, 19.84 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(sourced commercially) (7.53 g, 23.8 mmol) and Cs₂CO₃ (12.93 g, 39.7mmol) in 1,4-dioxane (187 mL) and water (75 mL. The reaction mixture washeated at 90° C. for 3 h. allowed to cool to rt and concentrated invacuo. The residue was taken up in water (1 L) and extracted with DCM(3×800 mL). The combined organic layers were washed with water, sat.brine, dried over MgSO₄, filtered and concentrated in vacuo. Theresulting crude product was purified by fcc, eluting with 0-15% MeOH inDCM. The product was taken up in MeCN (150 ml) and stirred for 2 h aftersonication. The resulting precipitate was isolated by filtration, washedwith diethyl ether and then n-heptane, and dried in vacuo to afford thetitle compound (6.30 g, 62%) as a pale cream solid; ¹H NMR (500 MHz,DMSO) 1.82-1.88 (1H, m), 2.10-2.14 (1H, m), 2.15 (3H, s), 2.30-2.34 (4H,m), 2.37-2.41 (4H, m), 2.47 (3H, s), 2.58-2.64 (1H, m), 2.64 (3H, s),2.75 (3H, s), 2.91-2.95 (2H, m), 3.23-3.26 (1H, m), 3.43-3.46 (1H, m),3.47 (2H, s), 3.64-3.67 (1H, m), 3.68-3.72 (1H, m), 7.32 (2H, d), 7.85(2H, d), 8.00 (1H, s), 8.56 (1H, s); m/z MH⁺ 512.

Example 60:(R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine

XPhos 2^(nd) generation precatalyst (24.45 mg, 0.03 mmol) was added to(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 46) (250 mg, 0.62 mmol),4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine(sourced commercially) (188 mg, 0.62 mmol) and Cs₂CO₃ (405 mg, 1.24mmol) in 1,4-dioxane (5 mL) and water (2.5 mL) at rt. The reactionmixture was stirred at 80° C. for 16 h, allowed to cool to rt, filteredthrough Celite and concentrated in vacuo. The resulting crude productwas purified by preparative HPLC to afford the title compound (191 mg,56%) as a pale yellow solid; ¹H NMR (300 MHz, MeOD) 1.93-2.02 (1H, m),2.18-2.28 (1H, m), 2.55 (3H, s), 2.65-2.74 (4H, m), 2.78-2.83 (7H, m),3.02-3.04 (2H, m), 3.29-3.35 (1H, m), 3.49-3.58 (1H, m), 3.66-3.81 (6H,m), 3.86 (2H, s), 7.47 (2H, d), 7.90 (2H, d), 7.99 (1H, s), 8.49 (1H,s); m/z MH⁺ 499.

Example 61:(R)-4-(4-(6-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyridazin-3-yl)benzyl)morpholine

XPhos 2^(nd) generation precatalyst (11 mg, 0.01 mmol) was added to(R)-6-((1-(6-chloropyridazin-3-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 53) (100 mg, 0.28 mmol),4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine(sourced commercially) (85 mg, 0.28 mmol) and Cs₂CO₃ (182 mg, 0.56 mmol)in 1,4-dioxane (2 mL) and water (1 mL) at rt. The reaction mixture wasstirred at 90° C. for 2 h, allowed to cool to rt and concentrated invacuo. The resulting crude product was purified by flash C18chromatography, eluting with 5-100% MeCN in water (+0.08% NH₄HCO₃), toafford the title compound (101 mg, 73%) as a white solid; ¹H NMR (400MHz, MeOD) 2.01 (1H, dq), 2.26 (1H, dt), 2.54 (7H, d), 2.75 (4H, s),2.86 (3H, s), 3.07 (2H, dd), 3.38 (1H, dd), 3.52-3.63 (3H, m), 3.68-3.86(6H, m), 7.04 (1H, d), 7.44-7.51 (2H, m), 7.82-7.95 (3H, m); m/z MH⁺499.

Example 62:(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine

Cs₂CO₃ (50 g, 153 mmol),4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine (10 g, 29.80 mmol)(Intermediate 65) and(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (Intermediate 58) (10 g, 29.80 mmol), RuPhos 3rdgeneration precatalyst (1.87 g, 2.24 mmol) and RuPhos (1.04 g, 2.24mmol) were combined. A degassed mixture of 2-methyltetrahydrofuran (80mL) and water (40 mL) was added and the reaction mixture was heated atreflux for 17 h, then allowed to cool to rt and diluted with DCM (250mL) and water (250 mL). The organic layer was isolated and washed with1:1 sat. brine:water (100 mL), then filtered through a pad of silica,then concentrated in vacuo to afford crude product. The reaction wasthen repeated using the following; Cs₂CO₃ (75 g, 230 mmol),4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine (15 g, 44.70mmol),(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (15 g, 44.7 mmol), RuPhos 3rd generation precatalyst(2.80 g, 3.35 mmol) and RuPhos (1.56 g, 3.35 mmol) in a degassed mixtureof 2-methyltetrahydrofuran (120 mL) and water (60 mL). The secondreaction was worked up in an identical way to that described to thefirst. The two batches of crude product were combined and purified bySFC (Kromasil SIL column 250×50 mm, 10 μm at a flow rate of 450 ml/minusing 33% MeOH in scCO₂ at 130 bar and oven temperature of 30° C.) toafford the title compound (29 g, 80% yield based on combining bothbatches) as a white solid; ¹H NMR (600 MHz, DMSO) 2.31 (1H, dtd), 2.42(5H, d), 2.46 (3H, s), 2.52 (3H, s), 2.58 (3H, s), 3.45 (1H, dd), 3.54(1H, td), 3.58 (5H, q), 3.62-3.68 (1H, m), 3.77 (2H, s), 4.96 (1H, s),6.74 (2H, d), 7.65 (1H, d), 8.03 (2H, d), 8.07 (1H, d); m/z MH⁺ 501.

Form A

The final product,(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine,was analysed by XRPD and DSC and found to be crystalline. XRPD of asample of the material gave rise to a diffraction pattern as shown inFIG. 1 .(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine,Form A is characterised by at least one peak at a 20 value of 7.8° or19.0°, measured using CuKα radiation. The ten most prominent peaks ofthe XRPD are shown in Table A.

TABLE A Ten most prominent XRPD peaks for Form A,(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine Angle 2-Theta (2θ)Intensity % 7.8 100 19.0 59 18.3 54.7 9.2 49.3 15.8 38.8 11.6 32.6 9.531.4 10.4 31.4 25.3 29.2 22.3 29

Example 62.1: Scale up of(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine1^(st) Arm of Convergence Route

Stage 1: 1-(4-bromophenyl)-1,4-pentanedione (Intermediate 63)

2-bromo-1-(4-bromophenyl)ethenone (12.2 Kg, 43.89 mol), 2,4-pentanedione(9.2 Kg, 91.89 mol), and potassium carbonate (12.2 Kg, 88.27 mol) wereslurried in ethanol (72.25 L) for approximately 24 h at roomtemperature. Ethyl acetate (84.26 L) and water (74 L) were added to givea phase separation, where the lower phase was discarded. Solventswapping the organic phase into n-heptane (2×84.8 L and 1×73.1 L)resulted in a solid, which was isolated by filtration, and washed withn-heptane (17.54 L) to afford the title compound (7.26 Kg, 59.4% yieldbased on assay value of 91.6% w/w). ¹H NMR (400 MHz, CDCl₃) 2.15 (3H,s), 2.56 (2H, t), 3.07 (2H, t), 7.44 (2H, d), 7.89 (2H, d).

Stage 2: 3-(4-bromophenyl)-6-methylpyridazine (Intermediate 64)

1-(4-bromophenyl)-1,4-pentadione (13.2 Kg, 51.74 mol) and hydrazinehydrate (10.9 Kg, 217.74 mol) were mixed in ethanol (54.5 L) forapproximately 6 h at room temperature. Addition of water gave a solidwhich was isolated by filtration and washed with water (3×66 L) andn-heptane (2×36.5 L). The solid was mixed withtetrachloro-1,4-benzoquinone (14.5 Kg, 58.97 mol) and acetonitrile(137.4 L) for approximately 6 h at room temperature. The reaction wasquenched with 12.5% w/w sodium sulfite solution (85 L), and theacetonitrile removed by distillation. Addition of water (66 L) and 2Msodium hydroxide solution (66 L) gave a solid which was isolated byfiltration and washed with 2M sodium hydroxide (2×40 L) and water (2×145L). The solid was mixed with dichloromethane (140 L) and again filteredbefore washing with water (3×145 L). The organic phase was then treatedwith activated carbon followed by a solvent swap into methyl tert-butylether (100 L) and finally washed with methyl tert-butyl ether (2×55 L).This afforded the title compound (8.25 Kg, 61% yield based on assayvalue of 95.2% w/w). ¹H NMR (400 MHz, CDCl₃) 2.75 (3H, s), 7.38 (1H, d),7.65-7.60 (2H, m), 7.71 (1H, d), 7.96-7.91 (2H, m); ¹³C NMR (400 MHz,CDCl₃) 22.1, 123.5, 124.4, 127.3, 128.4, 132.2, 135.4, 156.2, 158.6.

Stage 3: 4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine(Intermediate 65)

1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (2.8 Kg, 12.05 mol) wasadded portionwise to 3-(4-bromophenyl)-6-methylpyridazine (Intermediate64) (7.15 Kg, 27.32 mol) in DCM (338.35 L) at rt. The reaction mixturewas stirred at rt for 3 h then a further portion of1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (0.31 Kg, 1.33 mol) wasadded and the reaction mixture was stirred for 3 h at it. The reactionmixture was filtered, and the organic filtrate was washed with water (68L) before a solvent swap into acetonitrile (55 L). Morpholine (4.75 Kg,54.52 mol) was added and the mixture heated for 4 h before concentrationand filtration to give a solid which was washed with acetonitrile (6 L)and water (6 L). The solid was dissolved using 4N hydrochloric acid (7.5Kg) and water (45 L). The acidic solution was washed with ethyl acetate(2×2.5 L) before pH adjustment with 15% w/w sodium hydroxide (11 Kg) togive a solid which was isolated by filtration. This afforded the titlecompound (6.2 Kg, 67% yield based on assay value of 98.7% w/w). ¹H NMR(400 MHz, CDCl₃) 2.56 (4H, m), 3.73 (4H, m), 3.91 (2H, s), 7.64 (2H, m),7.73 (1H, d), 7.81 (1H, d), 7.96 (2H, m); m/z MH⁺ 334.

2^(nd) Arm of Convergence Route

Stage 4: 3-methyl-1H-1,2,4-triazol-5-amine

Aminoguananidine bicarbonate (17.7 Kg, 130.04 mol) was mixed with nitricacid (165 g, 2.62 mol) in acetic acid (29.8 L, 521.21 mol) for 64 h at90° C. The mixture was cooled and diluted with isopropyl acetate (30 L)and filtered to afford the title compound. The crude material (13.9 Kg,36.7% yield based on 33.7% w/w assay) was used directly in stage 5.

Stage 5: 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-ol(Intermediate 56)

2,4-pentanedione (5.6 Kg, 55.93 mol) and tetra-n-butylammonium bromide(0.9 Kg, 2.79 mol) were cooled in acetonitrile (39.44 L). Slow additionof trimethylsilyl chloride (7.3 Kg, 67.19 mol) and dimethylsulfoxide(4.4 Kg, 56.32 mol) gave the intermediate 3-chloro-2,4-pentanedione asan acetonitrile solution. To this solution is charged benzoic acid (4.9Kg, 40.12 mol) and diisopropylethylamine (8.6 Kg, 66.54 mol) to give2,4-dioxopentan-3-yl benzoate (Intermediate 54). Solvent swapping with2-methyl tetrahydrofuran (28.1 L) followed by washing with 5% sodiumsulfate was followed by addition of 3-methyl-1H-1,2,4-triazole-5-amine(12.8 Kg, 43.97 mol). Addition of acetic acid (32.19 L) and heating at90° C. for 20 hours gave2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl benzoate(Intermediate 55). Solvent swapping with toluene (25 L) and stirring atroom temperature with 5M Sodium Hydroxide (63 L) for 20 hours at roomtemperature afforded the title compound. Addition of 6M hydrochloricacid resulted in a solid which was isolated by filtration and washedwith water (16 L). The solid was slurried in water (40 L) and toluene(15 L) and filtered then washed with water (16 L) and dried to give 5.8Kg (94.6% w/w assay, 30.79 mol, 76.7% yield from benzoic acid).

Stage 6: Intermediate 58:(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (Intermediate 58)

Diisopropyl azodicarboxylate (6.9 Kg, 34.12 mol) in THF (14.62) wasadded dropwise to 2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-ol(4.55 Kg, 24.16 mol), tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate(5.3 Kg, 28.31 mol) and triphenylphosphine (7.3 Kg, 27.83 mol) in THF(85.49 L) at 0° C. and then stirred at room temperature for 20 h. Thiswas followed by a solvent swap into 2-methyl THF (46.84 L) and washingwith 25% w/w sodium chloride (2×22 Kg). The 2-methyl THF was removed bysolvent swapping into isopropyl alcohol (45 L) and the Boc group removedby addition of 15% hydrochloric acid in isopropyl alcohol (73.8 Kg) andstirring for 15 hours at room temperature. Cooling and addition of seed(R)-2,5,7-trimethyl-6-(pyrrolidine-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (120 g, 370 mmol) gives a solid which was isolated byfiltration, and washed with isopropyl alcohol. The solid was finallyslurried in ethyl acetate (45 L) before a final filtration and wash withethyl acetate (45 L) to give 5.35 Kg (74% w/w assay*, 16.01 mol, 66%yield). ¹H NMR (400 MHz, DMSO) 2.03-2.13 (1H, m), 2.22-2.28 (1H, m),2.51-2.54 (3H, m), 2.62 (3H, d), 2.74 (3H, s), 3.32-3.45 (3H, m),3.46-3.56 (1H, m), 4.90 (1H, s), 9.91 (2H, s); m/z MH⁺ 248. *Assay isbased on the free base equivalent.

Convergence Stage 7:(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine(Example 62)

Cs₂CO₃ (23.8 Kg g, 73.0 mol),4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)morpholine (4.89 Kg, 14.63mol) (Intermediate 65) and(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidinedihydrochloride (Intermediate 58) (4.33 Kg, 17.51 mol*),2-ditert-butylphosphino-2′-methylbiphenyl (0.23 Kg, 736 mmol) andtris(dibenzylidenacetone)dipalladium(0) (0.33 Kg, 360 mmol) werecombined. A degassed mixture of 2-methyltetrahydrofuran (80 L) and water(40 L) was added and the reaction mixture was heated at reflux for 24 h,then allowed to cool to rt and diluted with DCM (100 L) and water (50L). The reaction mixture was filtered and the organic phase was solventswapped into ethyl acetate to give 8.4 Kg of crude material. This wasdissolved in DCM (200 L) and washed sequentially with 2M hydrochloricacid (2×90 L), 2M sodium hydroxide (140 L), and 5% sodium thiosulphate(2×50 L). The resulting DCM solution is passed through a silica thiolresin (0.5 Kg) before solvent swapping into ethyl acetate to give 5 Kgof crude material. This was dissolved in DCM (25 L) and the correct FormA was generated by addition of n-heptane (25 L) with seed((R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholineForm A) used to control the nucleation point. Filtration, and drying(30° C.) afforded the title compound (4.06 Kg, 8.11 mol, 55% yield) as awhite solid; ¹H NMR (600 MHz, DMSO) 2.31 (1H, dtd), 2.42 (5H, d), 2.46(3H, s), 2.52 (3H, s), 2.58 (3H, s), 3.45 (1H, dd), 3.54 (1H, td), 3.58(5H, q), 3.62-3.68 (1H, m), 3.77 (2H, s), 4.96 (1H, s), 6.74 (2H, d),7.65 (1H, d), 8.03 (2H, d), 8.07 (1H, d); m/z MH⁺ 501. *Charge isstrength adjusted to the free base of Intermediate 58—bulk charge=5.85Kg of dihydrochloride salt.

Example 63:(S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine

Example 63 was prepared in a similar way to Example 62 in 3 steps fromcommercially available tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylateto afford the title compound (125 mg, 31% final step) as a white solid;¹H NMR (400 MHz, DMSO) 2.26-2.47 (9H, m), 2.52 (3H, s), 2.58 (3H, s),3.45 (1H, dd), 3.5-3.61 (6H, m), 3.61-3.69 (1H, m), 3.77 (2H, s), 4.96(1H, s), 6.73 (2H, d), 7.64 (1H, d), 8.04 (3H, dd); m/z MH⁺ 501.

Example 64:(R)-2,5,7-trimethyl-6-((1-(4-(6-(piperidin-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (593 mg, 1.82 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (150 mg, 0.61 mmol) and3-(4-bromophenyl)-6-(piperidin-1-ylmethyl)pyridazine (Intermediate 70)(202 mg, 0.61 mmol) in 2-methyltetrahydrofuran (1.6 mL) and water (0.8mL). The reaction was degassed and RuPhos 3rd generation precatalyst (38mg, 0.05 mmol) and RuPhos (21 mg, 0.05 mmol) were added. The reactionmixture was heated at reflux for 18 h, allowed to cool to rt and thendiluted with DCM (10 mL) and water (5 mL) and passed through a phaseseparating cartridge. The resulting DCM layer was concentrated in vacuo.The resulting crude product was purified by preparative HPLC to affordthe title compound (83 mg, 27%) as a white solid; ¹H NMR (400 MHz, DMSO)1.37-1.45 (2H, m), 1.52 (4H, p), 2.32 (1H, dt), 2.40 (5H, s), 2.47 (3H,s), 2.53 (3H, s), 2.59 (3H, s), 3.46 (1H, dd), 3.51-3.61 (2H, m), 3.66(1H, q), 3.74 (2H, s) 4.98 (1H, s), 6.75 (2H, d), 7.63 (1H, d), 8-8.07(3H, m); m/z MH⁺ 499.

Example 65:(R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (593 mg, 1.82 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (150 mg, 0.61 mmol) and3-(4-bromophenyl)-6-((4-methylpiperazin-1-yl)methyl)pyridazine(Intermediate 71) (211 mg, 0.61 mmol) in 2-methyltetrahydrofuran (1.6mL) and water (0.8 mL). The reaction was degassed and RuPhos 3rdgeneration precatalyst (38 mg, 0.05 mmol) and RuPhos (21 mg, 0.05 mmol)were added. The reaction mixture was heated at reflux for 18 h, allowedto cool to rt and then diluted with DCM (10 mL) and water (5 mL) andpassed through a phase separating cartridge. The resulting DCM layer wasconcentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (154 mg, 49%) as a creamsolid; ¹H NMR (400 MHz, DMSO) 2.16 (3H, s), 2.27-2.38 (5H, m), 2.38-2.48(8H, m), 2.53 (3H, s), 2.59 (3H, s), 3.46 (1H, dd), 3.51-3.61 (2H, m),3.66 (1H, q), 3.77 (2H, s), 4.97 (1H, s), 6.74 (2H, d), 7.62 (1H, d),8.01-8.09 (3H, m); m/z MH⁺ 514.

Example 66:2,5,7-trimethyl-6-(((3R)-1-(4-(6-((3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (494 mg, 1.52 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (125 mg, 0.51 mmol) and8-((6-(4-bromophenyl)pyridazin-3-yl)methyl)-3-methyl-3,8-diazabicyclo[3.2.1]octane(Intermediate 66) (189 mg, 0.51 mmol) in 2-methyltetrahydrofuran (1.6mL) and water (0.8 mL). The reaction was degassed and RuPhos 3rdgeneration precatalyst (31.7 mg, 0.04 mmol) and RuPhos (17.69 mg, 0.04mmol) were added. The reaction mixture was heated at reflux for 18 h,allowed to cool to it then diluted with DCM (10 mL) and water (5 mL) andpassed through a phase separating cartridge. The resulting DCM layer wasconcentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (121 mg, 44%) as a creamsolid; ¹H NMR (400 MHz, CDCl₃) 1.86 (2H, q), 2.05 (2H, dd), 2.23 (3H,s), 2.27-2.39 (3H, m), 2.46-2.54 (1H, m), 2.57-2.63 (8H, m), 2.65 (3H,s), 3.13 (2H, s), 3.48-3.65 (3H, m), 3.73-3.82 (1H, m), 3.87 (2H, s),4.85 (1H, s), 6.68 (2H, d), 7.74-7.82 (2H, m), 8.04 (2H, d); m/z MH⁺540.

Example 67:6-(((R)-1-(4-(6-(((R)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (494 mg, 1.52 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (125 mg, 0.51 mmol) and(R)-2-((6-(4-bromophenyl)pyridazin-3-yl)methyl)octahydropyrrolo[1,2-a]pyrazine(Intermediate 67) (189 mg, 0.51 mmol) in 2-methyltetrahydrofuran (1.6mL) and water (0.8 mL). The reaction was degassed and RuPhos 3rdgeneration precatalyst (31.7 mg, 0.04 mmol) and RuPhos (17.7 mg, 0.04mmol) were added. The reaction mixture was heated at reflux for 18 h,allowed to cool to rt and then diluted with DCM (10 mL) and water (5 mL)and passed through a phase separating cartridge. The resulting DCM layerwas concentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (33 mg, 12%) as a creamsolid; ¹H NMR (400 MHz, DMSO) 1.20-1.31 (1H, m), 1.66 (3H, ttd),1.87-2.06 (3H, m), 2.14 (1H, td), 2.25 (1H, td), 2.33 (1H, dtd), 2.42(1H, dd), 2.47 (3H, s), 2.53 (3H, s), 2.59 (3H, s), 2.73 (1H, d),2.86-2.98 (3H, m), 3.46 (1H, dd), 3.51-3.62 (2H, m), 3.62-3.71 (1H, m),3.77-3.87 (2H, m), 4.97 (1H, s), 6.75 (2H, d), 7.62 (1H, d), 8.05 (3H,t); m/z MH⁺ 540.

Example 68:6-(((R)-1-(4-(6-(((S)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (494 mg, 1.52 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (125 mg, 0.51 mmol) and(S)-2-((6-(4-bromophenyl)pyridazin-3-yl)methyl)octahydropyrrolo[1,2-a]pyrazine(Intermediate 68) (189 mg, 0.51 mmol) in 2-methyltetrahydrofuran (1.6mL) and water (0.8 mL). The reaction was degassed and RuPhos 3rdgeneration precatalyst (31.7 mg, 0.04 mmol) and RuPhos (17.7 mg, 0.04mmol) were added. The reaction mixture was heated at reflux for 18 h,allowed to cool to rt, then diluted with DCM (10 mL) and water (5 mL)and passed through a phase separating cartridge. The resulting DCM layerwas concentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (76 mg, 28%) as a creamsolid; ¹H NMR (400 MHz, DMSO) 1.20-1.32 (1H, m), 1.66 (3H, dqd),1.88-2.06 (3H, m), 2.14 (1H, td), 2.25 (1H, td), 2.3-2.37 (1H, m), 2.42(1H, d), 2.47 (3H, s), 2.53 (3H, d), 2.60 (3H, s), 2.73 (1H, d),2.85-2.98 (3H, m), 3.47 (1H, dd), 3.51-3.62 (2H, m), 3.66 (1H, q),3.77-3.87 (2H, m), 4.98 (1H, s), 6.75 (2H, d), 7.62 (1H, d), 8.01-8.09(3H, m); m/z MH⁺ 540.

Example 69:(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine

Cs₂CO₃ (401 mg, 1.23 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (101 mg, 0.41 mmol) and4-((5-(4-bromophenyl)pyrimidin-2-yl)methyl)morpholine (Intermediate 39)(137 mg, 0.41 mmol) in 2-methyltetrahydrofuran (1.4 mL) and water (0.7mL). The reaction was degassed and RuPhos 3rd generation precatalyst(25.7 mg, 0.03 mmol) and RuPhos (14.4 mg, 0.03 mmol) were added. Thereaction mixture was heated at reflux for 18 h, allowed to cool to rtthen diluted with DCM (10 mL) and water (5 mL) and passed through aphase separating cartridge. The resulting DCM layer was concentrated invacuo. The resulting crude product was purified by preparative HPLC toafford the title compound (82 mg, 40%) as a white solid; ¹H NMR (400MHz, CDCl₃) 2.34 (1H, dp), 2.47-2.55 (1H, m), 2.60 (3H, s), 2.61-2.65(7H, m), 2.65 (3H, s), 3.45-3.54 (2H, m), 3.58 (1H, td), 3.72-3.78 (1H,m), 3.78-3.83 (4H, m), 3.85 (2H, s), 4.83-4.89 (1H, m), 6.65-6.72 (2H,m), 7.46-7.53 (2H, m), 8.89 (2H, s); m/z MH⁺ 501.

Example 70:(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyrazin-2-yl)methyl)morpholine

Cs₂CO₃ (668 mg, 2.05 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (169 mg, 0.68 mmol) and4-((5-(4-bromophenyl)pyrazin-2-yl)methyl)morpholine (Intermediate 77)(228 mg, 0.68 mmol) in 2-methyltetrahydrofuran (2.3 mL) and water (1.1mL). The reaction was degassed and RuPhos 3rd generation precatalyst(42.9 mg, 0.05 mmol) and RuPhos (23.9 mg, 0.05 mmol) were added. Thereaction mixture was heated at reflux for 18 h, allowed to cool to rt,then diluted with DCM (10 mL) and water (5 mL) and passed through aphase separating cartridge. The resulting DCM layer was concentrated invacuo. The resulting crude product was purified by preparative HPLC toafford the title compound (104 mg, 30%) as a cream solid; ¹H NMR (400MHz, CDCl₃) 2.33 (1H, dtd), 2.50 (1H, dd), 2.53-2.57 (4H, m), 2.60 (3H,s), 2.61 (3H, s), 2.64 (3H, s), 3.46-3.6 (2H, m), 3.61 (1H, td), 3.70(2H, s), 3.72-3.83 (5H, m), 4.85 (1H, dt), 6.63-6.71 (2H, m), 7.91-8.00(2H, m), 8.60 (1H, d), 8.91 (1H, d); m/z MH⁺ 501.

Example 71:(R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one

Cs₂CO₃ (632 mg, 1.94 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (160 mg, 0.65 mmol) and1-(4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one(Intermediate 69) (243 mg, 0.65 mmol) in 2-methyltetrahydrofuran (1.7mL) and water (0.9 mL). The reaction was degassed and RuPhos 3rdgeneration precatalyst (40.6 mg, 0.05 mmol) and RuPhos (22.6 mg, 0.05mmol) were added. The resulting suspension was heated at reflux for 18h, allowed to cool to rt, diluted with DCM (10 mL) and water (5 mL) andpassed through a phase separating cartridge. The resulting DCM layer wasconcentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (154 mg, 44%) as a paleyellow solid; ¹H NMR (400 MHz, DMSO) 1.99 (3H, s), 2.33 (1H, d),2.37-2.43 (3H, m), 2.47 (5H, s), 2.53 (3H, s), 2.59 (3H, s), 3.46 (5H,dd), 3.56 (2H, q), 3.66 (1H, q), 3.82 (2H, s), 4.98 (1H, s), 6.75 (2H,d), 7.66 (1H, d), 8.06 (3H, dd); m/z MH⁺ 542.

Example 72:(R)-6-((1-(4-(6-((4-ethylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (336 mg, 1.03 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (85 mg, 0.34 mmol) and3-(4-bromophenyl)-6-((4-ethylpiperazin-1-yl)methyl)pyridazine(Intermediate 72) (124 mg, 0.34 mmol) in 2-methyltetrahydrofuran (0.9mL) and water (0.5 mL). The reaction was degassed and RuPhos 3rdgeneration precatalyst (21.6 mg, 0.03 mmol) and RuPhos (12.0 mg, 0.03mmol) were added. The reaction mixture was heated at reflux for 18 h,allowed to cool to rt, diluted with DCM (10 mL) and water (5 mL) andpassed through a phase separating cartridge. The resulting DCM layer wasconcentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (65 mg, 36%) as a paleyellow solid; ¹H NMR (400 MHz, CDCl₃) 1.08 (3H, t), 2.33 (1H, dtd), 2.42(3H, q), 2.45-2.54 (4H, m), 2.57-2.64 (10H, m), 2.65 (3H, s), 3.52 (2H,dd), 3.57-3.65 (1H, m), 3.78 (1H, td), 3.89 (2H, s), 4.85 (1H, dt), 6.68(2H, d), 7.60 (1H, d), 7.74 (1H, d), 8-8.08 (2H, m); m/z MH⁺ 528.

Example 73:(R)-6-((1-(4-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (870 mg, 2.67 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (220 mg, 0.89 mmol) and3-(4-bromophenyl)-6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazine(intermediate 73) (348 mg, 0.89 mmol) in 2-methyltetrahydrofuran (2.4mL) and water (1.1 mL). The reaction was degassed and RuPhos 3rdgeneration precatalyst (55.8 mg, 0.07 mmol) and RuPhos (31.1 mg, 0.07mmol) were added. The reaction mixture was heated at reflux for 18 h,allowed to cool to rt, diluted with DCM (10 mL) and water (5 mL) andpassed through a phase separating cartridge. The resulting DCM layer wasconcentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (211 mg, 43%) as a paleyellow foamy solid; ¹H NMR (400 MHz, CDCl₃) 2.33 (1H, dtd), 2.49 (1H,dd), 2.51-2.64 (16H, m), 2.65 (3H, s), 3.35 (3H, s), 3.46-3.56 (4H, m),3.57-3.64 (1H, m), 3.78 (1H, td), 3.89 (2H, s), 4.84 (1H, dd), 6.68 (2H,d), 7.59 (1H, d), 7.74 (1H, d), 8.00-8.07 (2H, m); m/z MH⁺ 558.

Example 74:(R)-4-((6′-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)-[2,3′-bipyridin]-5-yl)methyl)morpholine

To(R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 59) (190 mg, 0.47 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (144 mg,0.57 mmol) and potassium acetate (92 mg, 0.94 mmol) in 1,4-dioxane (5mL) in a microwave vial was added PdCl₂(dppf)-CH₂Cl₂ adduct (19 mg, 0.02mmol) and the reaction was heated at 90° C. overnight, then allowed tocool to rt. 4-((6-bromopyridin-3-yl)methyl)morpholine (Intermediate 30)(121 mg, 0.47 mmol) was added followed by Cs₂CO₃ (307 mg, 0.94 mmol),XPhos 2^(nd) generation precatalyst (74 mg, 0.05 mmol) and water (3 mL).The reaction mixture was heated at 90° C. for 18 h, then allowed to coolto rt and diluted with EtOAc (50 mL) and water (10 mL) and the layersseparated. The aqueous layer was further extracted with DCM (50 mL) andthe combined organic layers were dried over MgSO₄, filtered andconcentrated in vacuo. The resulting crude product was purified bypreparative HPLC to afford the title compound (44 mg, 19%) as a palebrown foam; ¹H NMR (400 MHz, CDCl₃) 2.34 (1H, dtd), 2.42-2.56 (5H, m),2.60 (3H, s), 2.61 (3H, s), 2.64 (3H, s), 3.53 (2H, s), 3.61 (1H, dd),3.68-3.73 (4H, m), 3.74-3.92 (3H, m), 4.82 (1H, s), 6.51 (1H, d), 7.60(1H, d), 7.70 (1H, dd), 8.21 (1H, dd), 8.55 (1H, d), 8.76 (1H, d) m/zMH⁺ 501.

Example 75:(R)-4-((6′-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)-[3,3′-bipyridin]-6-yl)methyl)morpholine

Cs₂CO₃ (242 mg, 0.74 mmol) was added to(6-(morpholinomethyl)pyridin-3-yl)boronic acid (83 mg, 0.37 mmol) and(R)-6-((1-(5-bromopyridin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 59) (150 mg, 0.37 mmol) in 1,4-dioxane (2.5 mL) and water(1.2 mL). The reaction was degassed and XPhos 2^(nd) generationprecatalyst (59 mg, 0.04 mmol) was added. The reaction mixture wasstirred at 80° C. for 18 h, allowed to cool to rt, diluted with DCM (10mL) and water (5 mL) and passed through a phase separating cartridge.The resulting DCM layer was concentrated in vacuo. The resulting crudeproduct was dissolved in DMSO (2 mL) and purified by preparative HPLC,then further purified by fcc, eluting with 0-3% 1 M NH₃/MeOH in DCM toafford the title compound (18 mg, 10%) as a colourless gum; ¹H NMR (400MHz, CDCl₃) 2.34 (1H, dtd), 2.48-2.53 (1H, m), 2.52-2.57 (4H, m), 2.60(3H, s), 2.62 (3H, s), 2.65 (3H, s), 3.60 (1H, dd), 3.69 (2H, s), 3.76(5H, h), 3.8-3.89 (2H, m), 4.83 (1H, dt), 6.48-6.54 (1H, m), 7.46 (1H,d), 7.72 (1H, dd), 7.78 (1H, dd), 8.41 (1H, dd), 8.74 (1H, dd); m/z MH⁺501.

Example 76:(R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(131 mg, 0.42 mmol),(R)-6-((1-(2-bromopyrimidin-5-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 61) (140 mg, 0.35 mmol) and Cs₂CO₃ (226 mg, 0.69 mmol)were added to 1,4-dioxane (3.7 mL) and water (1.8 mL) and the mixturewas degassed for 10 minutes. XPhos 2^(nd) generation precatalyst (13.62mg, 0.02 mmol) was added and the reaction mixture was stirred for 2 h at85° C., allowed to cool to rt and poured into water (25 mL), andextracted with EtOAc (2×50 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated in vacuo. The resulting crudeproduct was purified by preparative HPLC, then further purified by fcc,eluting with 0-5% 1 M NH₃/MeOH in DCM to afford the title compound (54mg, 30%) as a white foam; ¹H NMR (500 MHz, DMSO) 2.16 (3H, s), 2.24-2.46(9H, m), 2.48 (3H, s), 2.52-2.54 (1H, m), 2.55 (3H, s), 2.60 (3H, s),3.44-3.52 (3H, m), 3.57-3.64 (1H, m), 3.69 (2H, dd), 5.00 (1H, s), 7.37(2H, d), 8.18-8.24 (2H, m), 8.31 (2H, s); m/z MH⁺ 514.

Example 77:(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine

Palladium (II) acetate (3.2 mg, 0.01 mmol) was added to(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 62) (115 mg, 0.28 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(117 mg, 0.37 mmol), potassium phosphate (151 mg, 0.71 mmol) anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (13.6mg, 0.03 mmol) in degassed water (1.6 mL) and THF (5 mL) at rt. Thereaction mixture was heated at reflux for 1 h, allowed to cool to r,diluted with EtOAc (50 mL) and washed with water (50 mL). The organiclayer was isolated and dried over MgSO₄, filtered and concentrated invacuo. The resulting crude product was dissolved in DCM (1 mL) andpurified by fcc, eluting with 0-5% 1 M NH₃/MeOH in DCM to afford thetitle compound (83 mg, 57%) as a yellow foam; ¹H NMR (500 MHz, CDCl₃)2.29 (3H, s), 2.3-2.59 (10H, m), 2.60 (3H, s), 2.63 (3H, s), 2.66 (3H,s), 3.55 (2H, s), 3.63 (1H, dd), 3.78-3.93 (3H, m), 4.84 (1H, s), 7.41(2H, d), 7.79-7.88 (2H, m), 8.02 (1H, d), 8.53 (1H, d); m/z MH⁺ 514.

Example 78:(R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine

Palladium (II) acetate (6.9 mg, 0.03 mmol) was added to(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 62) (250 mg, 0.62 mmol),4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (225mg, 0.74 mmol), potassium phosphate (328 mg, 1.55 mmol) anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (29.5mg, 0.06 mmol) in degassed water (3.33 mL) and THF (10 mL) at rt. Thereaction mixture was heated at reflux for 1 h, allowed to cool to rt,diluted with EtOAc (50 mL) and washed with water (50 mL). The organiclayer was isolated and dried over MgSO₄, filtered and concentrated invacuo. The resulting crude product was dissolved in DCM (I mL) andpurified by fcc, eluting with 0-5% 1 M NH₃/MeOH in DCM to afford thetitle compound (58 mg, 19%) as a yellow foam; ¹H NMR (500 MHz, CDCl₃)2.35 (1H, dtd), 2.44-2.5 (4H, m), 2.50-2.58 (1H, m), 2.60 (3H, s), 2.62(3H, s), 2.66 (3H, s), 3.54 (2H, s), 3.63 (1H, dd), 3.70-3.75 (4H, m),3.82 (1H, td), 3.85-3.93 (2H, m), 4.83 (1H, d), 7.42 (2H, d), 7.81-7.88(2H, m), 8.02 (1H, d), 8.53 (1H, d); m/z MH⁺ 501.

Example 79:1-[4-[[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]methyl]-1,4-diazepan-1-yl]ethanone

(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (30 mg, 0.07 mmol), 1-(1,4-diazepan-1-yl)ethanone(19.9 mg, 0.14 mmol), DCM (2 mL) and AcOH (2 drops) were combined andthe reaction mixture was stirred at rt for 5 h. Sodiumtriacetoxyborohydride (45 mg, 0.21 mmol) was added and the reactionmixture was stirred at rt for 16 h. The resulting mixture was purifiedby preparative HPLC to afford the title compound (18 mg, 47%); ¹H NMR(400 MHz, DMSO) 1.71 (1H, s), 1.81 (1H, d), 1.87 (1H, dd), 2.00 (3H, d),2.14 (1H, dd), 2.48 (3H, s), 2.54-2.62 (4H, m), 2.65-2.69 (4H, m), 2.76(3H, s), 2.95 (2H, d), 3.25 (1H, dd), 3.41-3.52 (5H, m), 3.61-3.75 (4H,m), 7.37 (2H, dd), 7.89 (2H, dd), 8.04 (1H, d), 8.63 (1H, d); m/z MH⁺554.

Example 80:(R)-2,5,7-trimethyl-6-((1-(S-(4-(pyrrolidin-1-ylmethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

XPhos 2^(nd) generation precatalyst (19.56 mg, 0.02 mmol) was added to(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(200 mg, 0.50 mmol),1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidine(143 mg, 0.50 mmol) and Cs₂CO₃ (324 mg, 0.99 mmol) in degassed1,4-dioxane (4 mL) and water (2 mL) at rt. The reaction mixture wasstirred at 90° C. for 16 h, allowed to cool to rt and purified by flashC18 chromatography, eluting with 5-100% MeCN in water (+0.08% NH₄HCO₃)to afford the title compound (63 mg, 26%) as a pale yellow solid; ¹H NMR(400 MHz, MeOD) 1.85 (4H, p), 1.99 (1H, dq), 2.26 (1H, dq), 2.59 (7H,d), 2.75 (4H, s), 2.86 (3H, s), 3.05 (2H, dt), 3.33-3.42 (1H, m), 3.56(1H, dt), 3.66-3.85 (4H, m), 7.41-7.48 (2H, m), 7.81-7.90 (2H, m), 8.01(1H, d), 8.50 (1H, d); m/z MH⁺ 483.

Example 81:(R)-2,5,7-trimethyl-6-((1-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Bis(triphenylphosphine)palladium(II) chloride (137 mg, 0.19 mmol) wasadded to 2-bromo-5-(pyrrolidin-1-ylmethyl)pyridine (Intermediate 78)(470 mg, 1.95 mmol), 1,1,1,2,2,2-hexamethyldistannane (702 mg, 2.14mmol) in THF (6 mL) at rt. The reaction mixture was stirred at 85° C.for 16 h. The reaction mixture was transferred to a microwave vial and(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(300 mg, 0.75 mmol) and Pd(Ph₃P)₄ (86 mg, 0.07 mmol) were added. Thereaction mixture was heated at 100° C. for 5 h in a microwave reactorthen allowed to cool to rt. The resulting mixture was purified by flashC18 chromatography, eluting with 5-100% MeCN in water (+0.1% FA), thenfurther purified by preparative HPLC, eluting with decreasingly polarmixtures of water (containing 10 mmol NH₄HCO₃) and MeCN to afford thetitle compound (115 mg, 32%) as a pale yellow solid; ¹H NMR (400 MHz,MeOD) 1.86 (4H, p), 2.00 (1H, dq), 2.26 (1H, dq), 2.60 (7H, d), 2.75(4H, s), 2.86 (3H, s), 3.07 (2H, dd), 3.38 (1H, dd), 3.58 (1H, dt),3.71-3.88 (4H, m), 7.87 (1H, dd), 8.04 (1H, d), 8.14 (1H, d), 8.51-8.57(1H, m), 8.92 (1H, d); m/z MH⁺ 484.

Example 82:(R)-2,5,7-trimethyl-6-((1-(S-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

PdCl₂(dppf)-CH₂Cl₂ adduct (85 mg, 0.12 mmol) was added to5-bromo-2-(pyrrolidin-1-ylmethyl)pyridine (Intermediate 80) (560 mg,2.32 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(590 mg, 2.32 mmol) and potassium acetate (456 mg, 4.64 mmol) in1,4-dioxane (10 mL) at rt. The reaction mixture was stirred at 90° C.for 16 h, and allowed to cool to rt. The reaction mixture was purifiedby flash C18 chromatography, eluting with 5-100% MeOH in water to affordimpure2-(pyrrolidin-1-ylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(280 mg, 42% if pure) as a yellow solid. XPhos 2^(nd) generationprecatalyst (29.3 mg, 0.04 mmol) was added to(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(300 mg, 0.75 mmol), impure2-(pyrrolidin-1-ylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinefrom the first step (258 mg, 0.89 mmol if pure) and Cs₂CO₃ (486 mg, 1.49mmol) in 1,4-dioxane (4 mL) and water (2 mL) at rt. The reaction mixturewas stirred at 90° C. for 16 h. The crude product was purified by flashC18 chromatography, eluting with 5-100% MeCN in water (+0.1% FA), toafford the title compound (54 mg, 15%) as a pale yellow solid; ¹H NMR(400 MHz, MeOD) 1.87-2.07 (5H, m), 2.27 (1H, dq), 2.57 (3H, s),2.67-2.89 (1H, m), 3.07 (2H, dd), 3.34-3.42 (1H, m), 3.54-3.64 (1H, m),3.69-3.88 (2H, m), 3.98 (2H, s), 7.58 (1H, d), 8.08 (1H, d), 8.33 (1H,dd), 8.54-8.61 (1H, m), 9.06 (1H, dd); m/z MH⁺ 484.

Example 83:(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methyl-1,4-diazepan-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine

1-Methyl-1,4-diazepane (53 mg, 0.47 mmol) was added to(R)-4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzaldehyde(Intermediate 49) (200 mg, 0.47 mmol) in DCM (5 mL) at rt under air andthe reaction mixture was stirred for 1 h. Sodium triacetoxyborohydride(496 mg, 2.34 mmol) was added and the reaction mixture was stirred at rtfor 16 h, then concentrated in vacuo. The resulting crude product waspurified by flash C18 chromatography, eluting with 5-100% MeCN in water(+0.1% FA), to afford the formic acid salt of the title compound (129mg, 48%) as a white solid; ¹H NMR (400 MHz, CDCl₃) 1.88-2.02 (1H, m),2.08 (2H, dt), 2.25 (1H, dq), 2.60-2.76 (10H, m), 2.79-3.06 (11H, m),3.14-3.22 (2H, m), 3.35 (1H, dd), 3.58 (1H, dt), 3.69-3.84 (4H, m),7.38-7.45 (2H, m), 7.81-7.89 (2H, m), 7.97 (1H, d), 8.52 (1H, d), 8.60(1H, s); m/z MH⁺ 526.

Example 84:(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)-1,4-oxazepane

Cs₂CO₃ (553 mg, 1.70 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (140 mg, 0.57 mmol) and4-((6-(4-bromophenyl)pyridazin-3-yl)methyl)-1,4-oxazepane (intermediate74) (197 mg, 0.57 mmol) in 2-methyltetrahydrofuran (1.5 mL) and water(0.76 mL). The reaction was degassed and RuPbos 3rd generationprecatalyst (35.5 mg, 0.04 mmol) and RuPhos (19.8 mg, 0.04 mmol) wereadded. The reaction mixture was stirred at 88° C. for 18 h, allowed tocool to rt, diluted with DCM (10 mL) and water (5 mL) and passed througha phase separating cartridge. The resulting DCM layer was concentratedin vacuo. The resulting crude product was dissolved in DMSO (2 mL) andpurified by preparative HPLC to afford the title compound (136 mg, 47%)as a pale yellow solid; ¹H NMR (400 MHz, DMSO) 1.84 (2H, p), 2.35 (1H,tt), 2.43 (1H, dd), 2.48 (3H, s), 2.54 (3H, s), 2.60 (3H, s), 2.72 (4H,q), 3.47 (1H, dd), 3.56 (2H, dd), 3.60-3.69 (3H, m), 3.72 (2H, t), 3.95(2H, s), 4.98 (1H, s), 6.75 (2H, d), 7.69 (1H, d), 8.02-8.11 (3H, m);m/z MH⁺ 515.

Example 85:(R)-6-((1-(4-(6-(azepan-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

Cs₂CO₃ (249 mg, 0.76 mmol) was added to(R)-2,5,7-trimethyl-6-(pyrrolidin-3-yloxy)-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 58B) (63 mg, 0.25 mmol) and1-((6-(4-bromophenyl)pyridazin-3-yl)methyl)azepane (Intermediate 75) (88mg, 0.25 mmol) in 2-methyltetrahydrofuran (0.6 mL) and water (0.3 mL).The reaction was degassed and RuPhos 3rd generation precatalyst (16 mg,0.02 mmol) and RuPhos (9 mg, 0.02 mmol) were added. The reaction mixturewas stirred at 88° C. for 18 h, allowed to cool to rt, diluted with DCM(10 mL) and water (5 mL) and passed through a phase separatingcartridge. The resulting DCM layer was concentrated in vacuo. Theresulting crude product was dissolved in DMSO (2 mL) and purified bypreparative HPLC. The resulting product was loaded onto a 5 g SCXcolumn, washing with MeOH (2× column volumes) then eluting with 1 M NHin MeOH (2× column volumes), and concentrated in vacuo to afford thetitle compound (35 mg, 27%) as a white solid; ¹H NMR (400 MHz, DMSO)1.60 (8H, s), 2.3-2.37 (1H, m), 2.43 (1H, d), 2.48 (3H, s), 2.54 (3H,d), 2.61 (3H, s), 2.66 (4H, d), 3.48 (1H, dd), 3.52-3.63 (2H, m), 3.67(1H, q), 3.92 (2H, s), 4.99 (1H, s), 6.76 (2H, d), 7.68 (1H, d),8.01-8.11 (3H, m); m/z MH⁺ 513.

Examples 86 and 87:4-[(1R)-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholineand4-[(1S)-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine

Tetrakis(triphenylphosphine)palladium(0) (157 mg, 0.14 mmol) was addedto a degassed solution of4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)morpholine(sourced commercially) (432 mg, 1.36 mmol),(R)-6-((1-(5-bromopyrazin-2-yl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine(Intermediate 62) (550 mg, 1.36 mmol) and sodium carbonate (2.0 mL, 4.1mmol) in 1,4-dioxane (7.7 mL) and water (3.9 mL) under nitrogen. Theresulting solution was stirred at 80° C. for 2 hours then allowed tocool to rt. The reaction mixture was diluted with EtOAc (50 mL), andwashed sequentially with water (25 mL) and sat. brine (25 mL). Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The resulting crude product was purified by fcc, elution gradient 0-5%MeOH in DCM, to afford the title compound as a mixture of twodiastereomers (355 mg). The isomers were isolated by chiral SFC(Phenomonex C1, 30×250 mm, 5 micron column at a flow rate of 80 ml/minusing 40% IPA+0.1% DEA/60% scCO₂ at 120 bar and column temperature of40° C.) to afford a single diastereomer (unknown chirality alpha tomorpholine) of4-(1-(4-(5-((R)-3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pyrazin-2-yl)phenyl)ethyl)morpholine(62 mg, 18%); ¹H NMR (400 MHz, CDCl₃) 1.38 (3H, d), 2.28-2.47 (3H, m),2.47-2.58 (3H, m), 2.60 (3H, s), 2.62 (3H, s), 2.66 (3H, s), 3.35 (1H,q), 3.59-3.75 (5H, m), 3.77-3.96 (3H, m), 4.84 (1H, s), 7.40 (2H, d),7.84 (2H, d), 8.01 (1H, d), 8.52 (1H, d); m/z MH⁺ 515; followed by asecond diastereomer (unknown chirality alpha to morpholine) of4-(1-(4-(5-((R)-3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pyrazin-2-yl)phenyl)ethyl)morpholine(68 mg, 19%); ¹H NMR (400 MHz, CDCl₃) 1.38 (3H, d), 2.27-2.46 (3H, m),2.46-2.58 (3H, m), 2.60 (3H, s), 2.62 (3H, s), 2.66 (3H, s), 3.35 (1H,q), 3.57-3.76 (5H, m), 3.77-3.96 (3H, m), 4.84 (1H, s), 7.40 (2H, d),7.84 (2H, d), 8.01 (1H, d), 8.52 (1H, d); m/z MH⁺ 515.

The invention claimed is:
 1. A method for treating cancer inwarm-blooded animal in need of such treatment, which comprisesadministering to the warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² eachindependently represent hydrogen or methyl; X represents CH₂ or O; RingA and Ring B each independently represent a ring selected from phenyl,pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl, wherein each of RingA and Ring B are independently optionally substituted with one or moresubstituents selected from C₁₋₃ alkyl and C₁₋₃ alkoxy; Ring C representsa 5 to 9 membered monocyclic or bicyclic saturated heterocycloalkyloptionally containing one or more additional heteroatoms independentlyselected from O, N and S, wherein Ring C is optionally substituted withone or more substituents selected from C₁₋₃ alkyl, optionallysubstituted with methoxy or hydroxyl; dioxo, C₀₋₂ alkyl-C(O)N(Me)₂,C(O)C₁₋₂ alkyl and S(O)₂C₁₋₂ alkyl.
 2. The method of claim 1, wherein Xrepresents CH₂.
 3. The method of claim 1, wherein X represents O.
 4. Themethod of claim 1, wherein R¹ and R² are both hydrogen.
 5. The method ofclaim 1, wherein Ring C is selected from morpholinyl, piperazinyl,piperidinyl, thiomorpholinyl, diazabicyclooctanyl,octahydropyrrolo[1,2-a]pyrazinyl, pyrrolidinyl, diazepanyl, oxazepanyland azepanyl.
 6. The method of claim 1, wherein Ring A and Ring B areeach independently optionally substituted with one or more substituentsselected from methyl and methoxy.
 7. The method of claim 1, wherein RingC is optionally substituted with one or more substituents selected frommethyl optionally substituted with hydroxyl; ethyl optionallysubstituted with methoxy or hydroxyl; dioxo, C(O)N(Me)₂, CH₂C(O)N(Me)₂,C(O)Me and S(O)₂Me.
 8. The method of claim 1, wherein the compound ofFormula (I) is a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein X, R¹, R² andRing C are as defined in claim 1 and wherein D, E, G, J, L, M, Q and Reach independently represent N or CR³, wherein no more than two of D, E,G and J represent N and wherein no more than two of L, M, Q and Rrepresent N, and R³ represents hydrogen, C₁₋₃ alkyl or C₁₋₃ alkoxy. 9.The method of claim 1, wherein the compound of Formula (I) is a compoundof Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², X, RingA, Ring B and Ring C are as defined in claim
 1. 10. The method of claim8, wherein the compound of Formula (I) is a compound of Formula (Ic):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², X, D, E,G, J, L, M, Q, R, Ring A, Ring B and Ring C are as defined in claim 8.11. The method of claim 1, wherein the compound is selected from thegroup consisting of:(R)-4-((6′-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)-[3,3′-bipyridin]-6-yl)methyl)morpholine;(R)-2,5,7-trimethyl-6-((1-(6′-((4-methylpiperazin-1-yl)methyl)-[3,3′-bipyridin]-6-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-(4-(2-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-5-yl)benzyl)morpholine;(R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyridin-2-yl)pyrazin-2-yl)methyl)morpholine;(R)-2,5,7-trimethyl-6-((1-(6-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyridin-3-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((6-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyridin-2-yl)pyridazin-3-yl)methyl)morpholine;6-(((R)-1-(2-(4-(((S)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)pyridin-2-yl)methyl)morpholine;(R)-6-((1-(2-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(2-(2-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;6-(((R)-1-(2-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)—N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)acetamide;(R)-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethanol;(R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)piperazin-1-yl)ethenone;(R)-6-((1-(2-(4-((4-(2-methoxyethyl)piperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)benzyl)morpholine;(R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(4-(2-((4-methylpiperazin-1-yl)methyl)pyrimidin-5-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridin-3-yl)methyl)morpholine;(R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyrimidin-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyrazin-2-yl)methyl)morpholine;(R)-2,5,7-trimethyl-6-((1-(4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)phenyl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine;(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;(S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;(R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)-6-methylpyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;2,5,7-trimethyl-6-(((R)-1-(5-(4-(((3R,5S)-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;6-(((R)-1-(5-(4-(((R)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;6-(((R)-1-(5-(4-(((R)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;2,5,7-trimethyl-6-(((R)-1-(5-(4-(((2R,5R)-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;2,5,7-trimethyl-6-(((R)-1-(5-(4-(((2S,5R)-2,4,5-trimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;2,5,7-trimethyl-6-[[(3R)-1-[5-[4-(1-piperidylmethyl)phenyl]pyrazin-2-yl]pyrrolidin-3-yl]methyl]-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-6-((1-(5-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(5-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;6-(((R)-1-(5-(4-(((3R,5S)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;2-{4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazin-1-yl}ethanol;(R)-6-((1-(5-(4-((4-(2-methoxy)ethyl)piperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-6-((1-(5-(2-methoxy-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;{1-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperidin-4-yl}methanol;6-{[(3R)-1-(5-{4-[(1,1-dioxidothiomorpholin-4-yl]methyl)phenyl}pyrazin-2-yl)pyrrolidin-3-yl]methyl}-2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidine;2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperidin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin-3-yl})methyl)[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((6-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-3-yl)methyl)morpholine;64-((R)-1-(5-(4-(((S)-3,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((5-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)pyridin-2-yl)methyl)morpholine;6-(((R)-1-(5-(4-(((S)-2,4-dimethylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-(4-(3-methyl-5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine;2,5,7-trimethyl-6-({(3R)-1-[5-(4-{[4-(methylsulfonyl)piperazin-1-yl]methyl}phenyl)pyrazin-2-yl]pyrrolidin-3-yl}methyl)[1,2,4]triazolo[1,5-a]pyrimidine;(R)—N,N-dimethyl-2-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)acetamide;(R)-2,5,7-trimethyl-6-((1-(6-methyl-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;N,N-dimethyl-4-[4-(5-{(3R)-3-[(2,5,7-trimethyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl}pyrazin-2-yl)benzyl]piperazine-1-carboxamide;(R)-2,5,7-trimethyl-6-((1-(5-(3-methyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(5-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-1-(4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)piperazin-1-yl)ethenone;(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine;(R)-4-(4-(6-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)pyridazin-3-yl)benzyl)morpholine;(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;(S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;(R)-2,5,7-trimethyl-6-((1-(4-(6-(piperidin-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(4-(6-((4-methylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;2,5,7-trimethyl-6-(((3R)-1-(4-(6-((3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;6-(((R)-1-(4-(6-(((R)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;6-(((R)-1-(4-(6-(((S)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyrimidin-2-yl)methyl)morpholine;(R)-44(5-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyrazin-2-yl)methyl)morpholine;(R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one;(R)-6-((1-(4-(6-((4-ethylpiperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-6-((1-(4-(6-((4-(2-methoxyethyl)piperazin-1-yl)methyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((6′-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)-[2,3′-bipyridin]-5-yl)methyl)morpholine;(R)-4-((6′-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)-[3,3′-bipyridin]-6-yl)methyl)morpholine;(R)-2,5,7-trimethyl-6-((1-(2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-5-yl)pyrrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrolidin-3-yl)oxy)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-(4-(5-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)pyrazin-2-yl)benzyl)morpholine;1-[4-[[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]methyl]-1,4-diazepan-1-yl]ethenone;(R)-2,5,7-trimethyl-6-((1-(5-(4-(pyrrolidin-1-ylmethyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(5-(5-(pyrrolidin-1-ylmethyl)pyridin-2-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-64(1-(5-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methyl-1,4-diazepan-1-yl))methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)-1,4-oxazepane;(R)-6-((1-(4-(6-(azepan-1-ylmethyl)pyridazin-3-yl)phenyl)pyrrolidin-3-yl)oxy)-2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidine;4-[(1R)-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine;and4-[(1S)-1-[4-[5-[(3R)-3-[(2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy]pyrrolidin-1-yl]pyrazin-2-yl]phenyl]ethyl]morpholine.12. The method of claim 1, wherein the compound is selected from:(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;(R)-1-(4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)piperazin-1-yl)ethan-1-one;(R)-2,5,7-trimethyl-6-((1-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrazin-2-yl)pyrrolidin-3-yl)methyl)-[1,2,4]triazolo[1,5-a]pyrimidine;(R)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine;and(S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine.13. The method of claim 1, wherein the compound is(R)-44(6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine,or a pharmaceutically acceptable salt thereof.
 14. The method of claim1, wherein the compound is(S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine,or a pharmaceutically acceptable salt thereof.
 15. The method of claim1, wherein the compound is(R)-44(6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine.16. The method of claim 1, wherein the compound is(S)-4-((6-(4-(3-((2,5,7-trimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)oxy)pyrrolidin-1-yl)phenyl)pyridazin-3-yl)methyl)morpholine.17. The method of claim 1, wherein the compound is in crystalline formwith an XRPD substantially as shown in FIG. 1 , measured using CuKαradiation.
 18. The method of claim 1, wherein the warm-blooded animal isfurther administered with at least one pharmaceutically acceptableexcipient.
 19. The method of claim 1, wherein the cancer is non-smallcell lung cancer, for example, lung adenocarcinoma.
 20. The method ofclaim 19, wherein the non-small lung cancer is lung adenocarcinoma.